Abstract Background This Phase 2b study compared the efficacy and toxicity of belotecan and topotecan in recurrent ovarian cancer. Methods Patients with platinum-sensitive recurrent or platinum-resistant recurrent ovarian cancer (PRROC) were randomised 1:1 to receive belotecan 0.5 mg/m² or topotecan 1.5 mg/m² for five consecutive days every 3 weeks. The primary endpoint was overall response rate (ORR); secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity. Results A total of 140 (belotecan, n = 71; topotecan, n = 69) and 130 patients (belotecan, n = 66; topotecan, n = 64) were included in the intention-to-treat (ITT) and per-protocol (PP) populations. ORR did not differ significantly between the belotecan and topotecan groups (ITT, 29.6% versus 26.1%; PP, 30.3% versus 25%). Although PFS did not differ between the groups, belotecan was associated with improved OS compared with topotecan in the PP population (39.7 versus 26.6 months; P = 0.034). In particular, belotecan showed longer OS in PRROC and non-high-grade serous carcinoma (non-HGSC; PP, adjusted hazard ratios, 0.499 and 0.187; 95% confidence intervals 0.255–0.977 and 0.039–0.895). Furthermore, there were no differences in toxicities between the two groups. Conclusions Belotecan was not inferior to topotecan in terms of overall response for recurrent ovarian cancer. Clinical trial registration NCT01630018.