We have compared the cognitive, EEG, and neuroendocrine effects of single doses of umespirone (20 mg and 80 mg) with those of buspirone (30 mg) and placebo in double-blind, cross-over studies in 44 healthy men. The pattern and time-course of the cognitive effects with umespirone and buspirone were dissimilar. Peak effects of buspirone were seen shortly after dosing and then receded, whilst the effects of umespirone persisted for up to 23 h. Although both drugs objectively impaired attention, buspirone reduced subjective alertness, calmness, and contentedness, whilst umespirone increased subjective alertness and contentedness and showed potential to improve secondary verbal memory. The EEG effects of umespirone were different from those seen with buspirone; they included a decrease of power in the alpha 1 band and the beta bands in the frontocentral area and an increase in the delta and theta bands in the occipitotemporal area. Umespirone had a later onset of action than buspirone but its effects lasted longer. Similar transient increases in serum prolactin and growth hormone concentrations were seen with buspirone and 80 mg umespirone; umespirone 20 mg had no effect. Plasma concentrations of ACTH and adrenaline and serum concentrations of cortisol were unaffected by either dose of umespirone. There was some evidence that buspirone increased ACTH and cortisol concentrations in some cases, and that umespirone increased noradrenaline concentrations. The frequency of adverse events was higher with buspirone than with 80 mg of umespirone. At the lower dose of umespirone, the frequency was similar to that with placebo.