Objective: Sertraline has not been evaluated for premenstrual dysphoric disorder (PMDD) in women taking oral contraceptives (OCs). The primary objective of the study was to determine the efficacy and tolerability of sertraline, compared with placebo in women with PMDD receiving OCs. A secondary objective was to identify any drug interaction between sertraline and OCs through competition for microsomal hepatic enzymes.Methods: Eight women between 18 and 45 years of age completed daily diaries for two menstrual cycles. Women meeting DSM-IV criteria for PMDD after a single-blind washout were randomized to either sertraline (50–150 mg/day) or placebo for three menstrual cycles and were then crossed over to the other treatment arm for another three cycles.Results: Sertraline (125.0 ± 38.0 mg/day) was superior to placebo. Compared with placebo, sertraline-treated patients had lower total premenstrual scores (P <0.09); and investigators rated patients with less severe illness (P <0.05) and greater improvement (P <0.01) on global measures. The treatments did not differ in number of adverse events. In 3 of 8 patients, detectable sertraline and desmethylsertaline concentrations were still present at the third placebo treatment cycle.Conclusions: This pilot study is the first to report sertraline as effective and well tolerated in women with PMDD who receive OCs. It is also the first account of decreased clearance of sertraline and desmethylsertraline in some patients with concomitant OC use.