1. The acute and subchronic effects of dothiepin 75-150 mg and fluoxetine 20 mg on critical fusion frequency (CFF), sustained attention and actual driving performance were compared with those of placebo in a double-blind, cross-over study involving 18 healthy volunteers. Drugs and placebo were administered for 22 days in evening doses. Fluoxetine doses were constant but dothiepin doses increased on the evening of day 8. Performance was assessed on days 1, 8 and 22 of each treatment series. Subjective sleep parameters and possible side effects were recorded on visual analogue scales on alternate treatment days. 2. Dothiepin reduced sustained attention on day 1 by 6.7% (95% confidence interval (C1): -12.0 to -1.3%) and CFF on day 22 by 1.1 (CI: -2.2 to -0.1) Hz. Fluoxetine reduced sustained attention days 1, 8 and 22 of treatment by 7.4, 6.7 and 6.5% respectively (CI: -11.3 to -3.6; -14.3 to -1.5 and -9.5 to -3.4). CFF decreased linearly over days during fluoxetine treatment and significantly differed from placebo on day 22 with 1.2 Hz (CI: -2.3 to -0.2). Neither drug significantly affected driving performance. Whilst receiving dothiepin, subjects complained of drowsiness on days 1-3 of treatment (mean rank 5.6; CI: 2.0 to 9.2) and slept 43 min longer (CI: 8.2 to 76.2).(ABSTRACT TRUNCATED AT 250 WORDS)