We measured mast-cell tryptase in postmortem blood from 22 heroin addicts dying suddenly after injection. In 32%, the concentration of tryptase was elevated (> or = 10 micrograms/l), and the mean value of tryptase was significantly different from a control group dying from known, nonimmunologic causes (P < 0.05). The increased tryptase concentrations indicate that death was preceded by systemic mast-cell degranulation. All victims of drug deaths had morphine in blood, most below 0.2 microgram/ml. In 71% of the victims of drug-related deaths with tryptase values > or = 10 micrograms/l, the intermediate degradation product, 6-monoacetyl-morphine, was not found in blood, whereas this was the case in only two victims with values below that cutoff point. This indicates that those with high tryptase concentrations survived longer than those with lower values. No correlation was found between the IgE levels and tryptase in either group, supporting the hypothesis that tryptase release was not mediated by an allergic reaction. The well-known property of opiates to stimulate unspecifically the liberation of histamine and other constituents of mast-cell granules offers one explanation of our observations. The results suggest that many heroin fatalities are caused by an anaphylactoid reaction.