Gonadotropin-releasing hormone (GnRH) agonists have been shown to reduce symptoms of premenstrual syndrome (PMS). This randomized, placebo-controlled study examined the efficacy of the GnRH agonist, leuprolide acetate depot, in a clearly defined PMS sample versus women with premenstrual symptoms in combination with dysphoric symptoms throughout the cycle, termed the premenstrual exacerbation (PME) group. Evaluation included the Structured Clinical Interview for DSM-III-R, administered in the follicular phase, and the subject Penn Dally Symptoms Report (DSR) maintained throughout the study. Thirty-three eligible women were randomized to double-blind treatment and administered 3.75 mg of depot leuprolide or a placebo once a month for 3 months. The subjects were seen for efficacy evaluations at the end of each cycle. Outcome measures were the DSRs and the 17-item Hamilton Depression Rating Scale (HAM-D17). The PMS leuprolide subjects improved significantly compared with the PMS placebo and PME leuprolide groups. The PME leuprolide group, who had dysphoric symptoms throughout the cycle, did not improve. Depression symptoms were at clinical levels premenstrually in the PMS and PME groups; following treatment they remitted in the PMS group but not in the PME leuprolide subjects. Efficacy did not occur until after several months of leuprolide treatment, but there was no evidence that PMS symptoms worsened with the onset of treatment. These results replicate the findings in our preliminary open-label study. Leuprolide reduced PMS symptoms to minimal levels where symptoms were limited to the luteal phase. Leuprolide was not effective for women with ongoing dysphoric symptoms, suggesting that premenstrual depression may have mechanisms different from those of other dysphoric mood disorders.