Overdose, heroin rarely causes death alone, most overdoses are due to multi-drug use (particularly alcohol and/or benzodiazepines)
For intravenous users of heroin (and any other substance), the use of non-sterile needles and syringes and other related equipment leads to the risk of contracting blood-borne pathogens such as HIV and hepatitis, as well as the risk of contracting bacterial or fungal endocarditis and possibly Venous sclerosis
Poisoning from contaminants added to "cut" or dilute heroin
Chronic constipation
Heroin-induced toxic leukoencephalopathy (very rare, smokers only, probably due to a toxic byproduct of a cutting substance)
Addiction and constantly growing tolerance. Like all opioids, heroin quickly causes physical addiction. Because endorphin receptors increase in number under continuous stimulation, tolerance also increases quickly.
Many countries and local governments have begun funding programs that supply sterile needles to people who inject illegal drugs in an attempt to reduce these contingent risks and especially the contraction and spread of blood-borne diseases. The Drug Policy Alliance reports that up to 75% of new AIDS cases among women and children are directly or indirectly a consequence of drug use by injection. But despite the immediate public health benefit of needle exchanges, some see such programs as tacit acceptance of illicit drug use. The United States does not support needle exchanges federally by law, and although some state and local governments do support needle exchange programs, they continue to face harassment by police in most areas. Needle exchanges have been instrumental in arresting the spread of HIV/AIDS in many communities with a significant heroin using population[citation needed], Australia being a leader due to its early inception of needle exchanges. Needle exchange programs have also been attributed to saving the public significant amounts of tax dollars by preventing medical costs which would have been required otherwise for the treatment of diseases spread through the practice of sharing and reusing needles.

A heroin overdose is usually treated with an opioid antagonist, such as naloxone (Narcan) or naltrexone, which have a high affinity for opioid receptors but do not activate them. This blocks heroin and other opioid agonists and causes an immediate return of consciousness and the beginning of withdrawal symptoms when administered intravenously. The half-life of these antagonists is usually much shorter than that of the opiate drugs they are used to block, so the antagonist usually has to be re-administered multiple times until the opiate has been metabolized by the body.

Depending on drug interactions and numerous other factors, death from overdose can take anywhere from several minutes to several hours due to anoxia because the breathing reflex is suppressed by µ-opioids. An overdose is immediately reversible with an opioid antagonist injection. Heroin overdoses can occur due to an unexpected increase in the dose or purity or due to diminished opiate tolerance. However, most fatalities reported as overdoses are probably caused by interactions with other depressant drugs like alcohol or benzodiazepines.

The LD50 for a person already addicted is prohibitively high, to the point that there is no general medical consensus on where to place it. Several studies done in the 1920s gave addicts doses of 1,600–1,800 mg of heroin in one sitting, and no adverse effects were reported. This is approximately 160–180 times a normal recreational dose. Even for a non-addict, the LD50 can be credibly placed above 350 mg.

Street heroin is of widely varying and unpredictable purity. This means that an addict may prepare what they consider to be a moderate dose while actually taking far more than intended. Also, relapsing addicts after a period of abstinence have tolerances below what they were during active addiction. If a dose comparable to their previous use is taken, an effect greater to what the user intended is caused, in extreme cases an overdose could result.

It has been speculated that an unknown portion of heroin related deaths are the result of an overdose or allergic reaction to quinine, which may sometimes be used as a cutting agent.

A final source of overdose in addicts comes from place conditioning. Heroin use, like other drug abuse behaviors, is highly ritualized. While the mechanism has yet to be clearly elucidated, it has been shown that longtime heroin users, immediately before injecting in a common area for heroin use, show an acute increase in metabolism and a surge in the concentration of opiate-metabolizing enzymes. This acute increase, a reaction to a location where the addict has repeatedly injected heroin, imbues the addict with a strong (but temporary) tolerance to the toxic effects of the drug. When the addict injects in a different location, this place-conditioned tolerance does not occur, giving the addict a much lower-than-expected ability to metabolize the drug. The user's typical dose of the drug, in the face of decreased tolerance, becomes far too high and can be toxic, leading to overdose.

A small percentage of heroin smokers may develop symptoms of toxic leukoencephalopathy. This is believed to be caused by an uncommon adulterant that is only active when heated. Symptoms include slurred speech and difficulty walking.