There has been considerable interest in the possibility that some psychotropic medications may possess antiviral activity. Several clinical observations suggest that lithium may inhibit the reactivation of latent herpes simplex virus, thereby reducing the number of recurrent infections. We performed a retrospective study examining the putative antiviral activity of various psychotropic agents in 177 subjects receiving lithium prophylaxis and a comparison group of 59 subjects receiving other antidepressant drugs for affective illness. Chronic lithium administration resulted in a significant reduction in the mean rate of recurrent labial herpes infections when compared to the pretreatment period (p less than 0.001). In contrast, the mean rate of herpes infections was unchanged in patients taking other antidepressants (p = 0.53). Although the overall reduction in herpes infections was not significantly different between groups, the proportion of subjects reporting a reduction in infection rate was greater in the lithium group (71%) compared with those receiving other antidepressants (52%) (p = 0.07). These data compliment prior in vitro and clinical studies demonstrating a potential antiviral activity for lithium carbonate.