BACKGROUND First-generation H1-receptor antagonists are popularly used for alleviating allergy and cold symptoms, but these antihistaminics cause drowsiness and sedation. Such side effects could impair performance and, thus, could be the cause or a factor in accidents. Therefore, the prevalence of these antagonists was evaluated in aviation accident pilot fatalities. METHODS The Civil Aerospace Medical Institute's (CAMI's) Toxicology Database was examined for the presence of the first-generation antihistamines in pilot fatalities of civil aircraft accidents that occurred during a 16-yr (1990-2005) period. RESULTS Of 5383 fatal aviation accidents from which CAMI received specimens, there were 338 accidents wherein pilot fatalities (cases) were found to contain brompheniramine, chlorpheniramine, diphenhydramine, doxylamine, pheniramine, phenyltoloxamine, promethazine, and triprolidine. Of the 338 accidents, 304 were general aviation accidents, and 175 of the 338 pilots held private pilot airman certificates. Antihistamines were detected alone in 103 fatalities (1 antihistamine in 94 and 2 antihistamines in 9), while other drug(s) and/or ethanol were also present in an additional 235 fatalities. The antihistamines were found in approximately 4 and 11% of the fatalities/accidents in 1990 and in 2004, respectively. The use of antihistamine(s) was determined by the National Transportation Safety Board to be the cause of 13 and a factor in 50 of the 338 accidents. CONCLUSIONS There was an overall increasing trend in the use of antihistamines by aviators during the 16-yr span. Blood levels of the antihistaminics were in the sub-therapeutic to toxic range. Findings from this study will be useful in investigating future accidents involving antihistamines.