Background: Cytoreductive surgery and systemic therapy are essential for newly diagnosed ovarian cancer. We conducted a multicenter phase 3 trial to study whether the addition of intraperitoneal chemotherapy under hyperthermic conditions (HIPEC) to interval cytoreductive surgery would improve outcome among patients receiving neo-adjuvant chemotherapy for stage III epithelial ovarian cancer. Methods: We randomly assigned patients who showed at least stable disease after three cycles of carboplatin (area under the curve 6) and paclitaxel (175 mg/m²) to receive interval cytoreductive surgery with or without HIPEC using cisplatin (100 mg/m²). Randomization was performed per-operatively and eligible patients had no residual mass greater than 2.5 mm. Three additional cycles of carboplatin and paclitaxel were given post-operatively. The primary endpoint was recurrence-free survival. Overall survival, toxicity, and quality-of-life were key secondary endpoints. Results: A total of 245 patients were randomly assigned to one of the two treatment strategies. In an intention-to-treat analysis, interval cytoreductive surgery with HIPEC was associated with longer recurrence-free survival than interval cytoreductive surgery alone (15 vs. 11 months, respectively; hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.49 to 0.86; P=0.003). At the time of analysis, 49% of patients were alive, with a significant improvement in overall survival favoring HIPEC (48 vs. 34 months; HR, 0.64; 95% CI, 0.45 to 0.91, P=0.01). The number of patients with grade 3-4 adverse events was similar in both treatment arms (28% vs. 24%, p=0.61). Quality-of-life analysis will follow. Conclusions: The addition of HIPEC to interval cytoreductive surgery is well tolerated and improves recurrence free and overall survival in patients with stage III epithelial ovarian cancer. Clinical trial information: NCT00426257