Administration of an alkylating agent plus a platinum coordination complex is standard therapy for advanced epithelial ovarian cancer in the United States. The most commonly used combination is cyclophosphamide/ cisplatin; however, the benefit of this combination in overall survival has not been compelling. We report a prospective comparison of this regimen versus a combination of cisplatin with paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), a new and well-tolerated agent with documented activity in cisplatin-refractory ovarian cancer. Three hundred eighty-six patients with advanced ovarian cancer and greater than 1 cm residual masses following initial surgery were randomly assigned to receive a regimen of cisplatin (75 mg/m2) and cyclophosphamide (750 mg/m2), or cisplatin (75 mg/m2) and paclitaxel (135 mg/m2), delivered over 24 hours. Dose reductions in cyclophosphamide or paclitaxel were permitted for significant toxicity. In 216 patients with measurable disease, responses were reported in 73% of those randomized to the cisplatin/paclitaxel arm and in 60% randomized to the cisplatin/cyclophosphamide arm. Progression-free survival was significantly longer (P < .001) with cisplatin/paclitaxel (median, 12.9 v 17.9 months). Overall survival was also significantly longer (P < .001) with cisplatin/paclitaxel (median, 37.5 v 24.4 months). Incorporating paclitaxel into first-line therapy for patients with suboptimally debulked stage III and stage IV ovarian cancer can increase the duration of the progression-free interval and extend overall survival while maintaining an acceptable toxicity profile.