The radiopharmaceutical [(131)I]meta-iodobenzylguanidine ([(131)I]MIBG) and the topoisomerase I inhibitor topotecan are both effective as single-agent treatments of neuroblastoma. Our purpose was to assess the therapeutic potential of [(131)I]MIBG and topotecan in combination using SK-N-BE(2c) neuroblastoma cells and UVW/NAT glioma cells expressing the noradrenaline transporter transgene. Topotecan treatment was given (i) before, (ii) after or (iii) simultaneously with [(131)I]MIBG. DNA fragmentation was evaluated by comet assay and cell cycle redistribution was determined by fluorescence-activated cell sorting. Combination index analysis indicated that delivery schedules (ii) and (iii) were more effective than schedule (i) with respect to clonogenic cell kill. Similarly, significant DNA damage was observed following treatment schedules (ii) and (iii) (p <0.005), but not (i). Prior exposure to topotecan did not significantly enhance [(131)I]MIBG uptake in athymic mice bearing tumour xenografts. We conclude that the enhancement of the efficacy of [(131)I]MIBG by combining it with topotecan was the result of inhibition of DNA damage repair rather than an increase in expression of the noradrenaline transporter by tumour.