Direct dissolution of the bulk material, capsule, or freeze-dried solution for injection and an internal standard in chloroform-d and recording of the PMR spectra provides a simple, specific, and accurate assay method form diphenhydramine hydrochloride [2-(diphenyl-methoxy)-N,N-dimethylethanamine hydrochloride] in pharmaceutical samples. The drug content can be calculated from the integral values for the N-methyl protons of diphenhydramine at ca. 2.85 ppm and for the methyl protons of tert-butyl alcohol at ca. 1.27 ppm. The mean +/- SD% recoveries from synthetic mixtures simulating capsules and injectables were 100.0 +/- 0.2 (n = 11) and 100.1 +/- 0.4 (n = 4), respectively. The method also permits the detection of degradation of diphenhydramine such as benzhydrol, diphenylchloromethane, and 2-(dimethylamino)ethanol to a minimum of about 2% of the parent compound.