Research into the psychobiology of premenstrual dysphoric disorder (PDD) finds alterations in markers associated with serotonergic neurotransmission. Supporting this is work showing that patients with PDD respond to some agents that block the reuptake of serotonin. In this open trial, patients were treated for one cycle with placebo and then for three consecutive cycles with the serotonin reuptake inhibitor paroxetine. The study population was composed of 14 participants who met DSM-IV criteria for PDD with moderate to severe symptomatology and specifically endorsed anger and irritability as a central premenstrual complaint. Patients showed modest improvement over the course of the pretreatment evaluation, with significant improvement occurring for feelings of worthlessness, decreased interest, and low energy. The effects of active treatment were marked by the first active cycle with luteal phase 17-item Hamilton Rating Scale for Depression scores decreasing from 14.9 (+/- 5.3) to 8.2 (+/- 4.9) in the first, 7.8 (+/- 5.1) in the second, and 7.8 (+/- 6.8) in the third active treatment cycles (F[1,13] = 17.6; p < 0.0001). A group of items from daily ratings indicative of anger and irritability (mood swings, anger and irritability, behavioral dyscontrol, and interpersonal conflicts) also showed improvement (F[1,13] = 5.94; p < 0.03). Various definitions of response were applied to treatment completers. The most conservative measure, the Clinical Global Impression (CGI), revealed that 7 of 14 patients had a complete response (CGI = 1 or 2) whereas 4 patients had a partial response (CGI = 3). These open trial findings are consistent with the notion that paroxetine is effective in the acute phase for the treatment of PDD.