BACKGROUND: Reports of responses and toxicities of salvage therapies for relapsed neuroblastoma are rare and often confounded by effects of additional treatments. Our objective was to describe the outcomes and toxicities for a topotecan and cyclophosphamide (TOPO/CTX) regimen for first relapse or progression of high-risk neuroblastoma. METHODS: We retrospectively reviewed charts of relapsed or refractory neuroblastoma patients treated between 1999 and 2009 with our standard-of-care outpatient TOPO/CTX (0.75 and 250 mg/m(2) /day x 5 days q3-4 weeks). RESULTS: Twenty-seven patients received 343 cycles of TOPO/CTX (median 10 cycles per patient, range 1-32). Most patients (N = 25) had undergone autologous stem cell transplantation. Seventeen (63%) patients had an objective response (CR + PR + MR). The 3-year progression-free survival (PFS) after relapse was 11 +/- 6% and 3-year overall survival (OS) after relapse was 33 +/- 9%. The median PFS was 1.2 years and the median OS was 2.3 years. Five patients are alive with follow-up of 3.1-5.5 years. Shorter time from diagnosis to relapse (6-18 months) was associated with shorter OS. The majority of patients experienced chemotherapy delays, transfusions, and febrile neutropenia, including eight bacterial infections. The mean number of hospitalized days was less than one per cycle. CONCLUSIONS: TOPO/CTX was well tolerated and resulted in response rates and PFS similar to those reported for patients treated on COG 9462. Our study provides additional toxicity, historical endpoints, and time-to-progression data against which new agents and combination therapies using TOPO/CTX as a backbone can be measured.