Background: Belotecan is a camptothecin derivative with anti-tumor properties. Previous studies suggested the feasibility of belotecan-based chemotherapy for patients with primary or recurrent ovarian cancer. Thus, we conducted a phase IIb trial to compare the efficacy and safety between belotecan and another derivative of camptothecin, topotecan, in patients with recurrent or refractory ovarian cancer. Methods: Patients with recurrent or refractory ovarian cancer were randomized to receive belotecan 0.5 mg/m² (B-arm) or topotecan 1.5 mg/m²(T-arm) intravenously for 5 consecutive days every 3 weeks till 6 cycles or disease progression. The primary endpoint was overall response rate based on RECIST or GCIG criteria, and secondary endpoints were progression-free survival (PFS), overall survival (OS) and adverse events according to NCI-CTCAE version 4.0. Results: One hundred and forty one patients were randomized from January 2011 to June 2014. Among all patients, 140 were eligible in full analysis (FA) set where patients received at least one dose (B-arm, n = 71; T-arm, n = 69), and 130 were eligible in per protocol (PP) set where patients completed the study protocol (B-arm, n = 66; T-arm, n = 64). Clinico-pathologic characteristics were not different between the two arms. ORR was not different between B- and T-arms in FA and PP sets (29.6% vs. 26.1%, p = 0.645; 30.3% vs. 25%, p = 0.499). Median values of PFS in B- and T-arms were 26.4 vs. 17.3 months in FA (HR = 0.69; 95% CI 0.41-1.16) and PP sets (HR = 0.68; 95% CI 0.39-1.16) without significant difference. However, OS was improved in B- versus T-arm in FA set with marginal significance (median values, 37.1 vs. 21.3 months, log-rank p = 0.053; HR = 0.60; 95% CI 0.35-1.01), and PP set (median values, 37.1 vs. 24.9 months, log-rank p = 0.023; HR = 0.53; 95% CI 0.31-0.93). Grade 3 or 4 adverse events were not different between the two arms. Conclusions: Belotecan may have a similar response and toxicity rates to topotecan in patients with recurrent or refractory ovarian cancer. Moreover, belotecan may prolong OS when compared with topotecan in these patients. Clinical trial information: NCT01630018