Several poisonings by diphenhydramine were reported shortly after it had been introduced as an antihistamine in 1945. In the Federal Republic of Germany its combination with 8-chlorotheophylline (dimenhydrinate) is available as a hypnotic without prescription. Replacing the dangerous diethylpentenamide diphenhydramine is a drug which is also often abused. Fatal poisonings, suicide attempts, and traffic accidents were increasingly observed. In seven cases drug-influenced road users caused traffic accidents. We observed blood concentrations of diphenhydramine as high as in four cases of clinically treated patients after ingestion of large doses. This indicates a serious drug abuse. The measurement of the concentration of diphenhydramine and its major metabolite (diphenmethoxy acetic acid) in blood and urine is a means of recognizing chronic use and misuse of diphenhydramine. As the metabolite accumulates in blood one may find an elevated level after multiple dosing. Shortly after taking a single dose no or only low metabolite concentration is found. The concentration of diphenhydramine and its metabolite was measured in several fatal cases. In one of these cases the concentration in body fluids and tissues was in a range not observed until now.