Serotonin reuptake inhibitors and calcium supplements ameliorate symptoms of premenstrual syndrome. A comparison of these agents to placebo may guide treatment selection. The goal of this pilot study was to compare fluoxetine and calcium to placebo.We enrolled 39 women with at least 3 moderate to severe premenstrual symptoms and functional impairment. The trial compared fluoxetine (10 mg twice daily), calcium carbonate (600 mg twice daily), and placebo over the course of 4 menstrual cycles. The Inventory of Depressive Symptomatology, Premenstrual Tension Scale, Clinical Global Impression–Severity and –Improvement scales, and Daily Record of Severity of Problems were used to measure symptoms.Symptom improvement was greatest for the fluoxetine group, although significance was achieved only for the Daily Record of Severity of Problems (β = −0.28; 95% confidence interval, −1.70 to −0.35; P = 0.02) and the Clinical Global Impression–Improvement (β = −1.03; 95% confidence interval= −1.70 to −0.35; P = 0.04). The Cohen d effect sizes for fluoxetine relative to placebo were between 0.80 and 2.08, whereas the effect sizes for calcium were only between 0.10 and 0.44.Fluoxetine had clear therapeutic benefit for premenstrual syndrome, whereas the effect of calcium was much smaller. Results of this pilot do not support the need for a larger study that would compare these compounds.