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PurposeWe report the results of the French multicentric phase II study MIITOP (NCT00960739), which evaluated tandem infusions of 131I‐metaiodobenzylguanidine (mIBG) and topotecan in children with relapsed/refractory metastatic neuroblastoma (NBL).MethodsPatients received 131I‐mIBG on day 1, with intravenous topotecan daily on days 1–5. A second activity of 131I‐mIBG was given on day 21 to deliver a whole‐body radiation dose of 4 Gy, combined with a second course of topotecan on days 21–25. Peripheral blood stem cells were infused on day 31.ResultsThirty patients were enrolled from November 2008 to June 2015. Median age at diagnosis was 5.5 years (2–20). Twenty‐one had very high‐risk NBL (VHR‐NBL), that is, stage 4 NBL at diagnosis or at relapse, with insufficient response (i.e., less than a partial response of metastases and more than three mIBG spots) after induction chemotherapy; nine had progressive metastatic relapse. Median Curie score at inclusion was 6 (1–26). Median number of prior lines of treatment was 3 (1–7). Objective response rate was 13% (95% confidence interval [CI]: 4–31) for the whole population, 19% for VHR‐NBL, and 0% for progressive relapses. Immediate tolerance was good, with nonhematologic toxicity limited to grade‐2 nausea/vomiting in eight patients. Two‐year event‐free survival was 17% (95% CI: 6–32). Among the 16 patients with VHR‐NBL who had not received prior myeloablative busulfan‐melphalan consolidation, 13 had at least stable disease after MIITOP; 11 subsequently received busulfan‐melphalan; four of them were alive (median follow‐up: 7 years).ConclusionMIITOP showed acceptable tolerability in this heavily pretreated population and encouraging survival rates in VHR‐NBL when followed by busulfan‐melphalan.