Many drugs, especially when given in rapid sequence can cause histamine release. Ten healthy volunteers were premedicated with diazepam 10 mg.70 kg-1 i.v. and lormetazepam 1 mg.70 kg-1 i.v., respectively, 30 min prior to etomidate 0.15 mg.kg-1 i.v. in a single-blind, crossover study. The benzodiazepine lormetazepam and the hypnotic etomidate caused distinct increases in histamine plasma levels in two subjects. Maximal histamine levels after lormetazepam were 2.05 and 2.7 ng.ml-1, and after etomidate 1.85 and 3.2 ng.ml-1, respectively. Both drugs are solved in propylene glycol, a solvent that conveys very high osmolality (lormetazepam 6,750 mosm.kg-1, etomidate 4,900 mosm.kg-1). Clinical symptoms, like tachycardia, hypotension or allergic reactions, associated with similar histamine levels were not seen in either case. This limited histamine release appears to be caused by osmotic damage of tissue and blood cells.