Eighteen healthy volunteers participated in a randomized, double blind, cross-over trial. They received mirtazapine, mianserin or placebo during separate periods of 15 days. Mirtazapine and mianserin were respectively administered in doses of 15 mg and 30 mg nocte for the ยฎrst 7 days and doses of 30 mg and 60 mg nocte for the remaining 8 days. Assessments were made at baseline and on days 2, 8, 9 and 16 of each period to compare eects of drugs and placebo on mood, psychomotor (CTT, CRT, CFF and Vigilance) and `actual' driving performance. Sleep quality and duration and side-eects were assessed at baseline and every treatment day. Mirtazapine 15 mg and mianserin 30 mg slightly impaired psychomotor and driving performance on day 2 of treatment. On day 8, the eects were virtually gone, although some driving impairment could still be observed in the mianserin condition. No drug eects on performance were found on day 9 despite the dose escalation. On day 16 of treatment, driving performance and vigilance slightly decreased in, respectively, the mirtazapine and the mianserin conditions. These eects indicate that tolerance to the drugs' adverse eects was not complete. This observation was also supported by subjective data. Similar increments in sleep duration and feelings of lethargy, drowsiness and weakness were observed throughout treatment with both drugs. Alertness and contentedness was always lower during both drug treatments than with placebo. Spontaneously reported adverse events were similar to self-rated side-eects and more of both were recorded during mianserin treatment. It is concluded that the acute and subchronic eects of nocturnal doses of both drugs were similar and equally low in magnitude. Eects on performance were much less than those seen in other studies after administration during the day. Full daily doses of both drugs should be prescribed in nocturnal dosing regimens, and not in divided doses over the day, for avoiding excessive sedation and performance impairment.