Background: Patients with relapsed or refractory neuroblastoma have a poor prognosis; there are limited effective and safe rescue chemotherapies for these patients. Development of new chemotherapy regimens for these patients is a key imperative. Procedure: We retrospectively analyzed patients with refractory or relapsed neuroblastoma who received irinotecan, etoposide, and carboplatin (IREC) as a second-line treatment for neuroblastoma. We evaluated the therapeutic response, toxicity, and survival outcomes. We also assessed the impact of UGT1A1 gene polymorphisms, which are involved in irinotecan metabolism, on the outcomes and toxicity. Results: A total of 131 cycles of IREC were administered to 43 patients with a median of two cycles per patient (range, 1–10). All patients were classified as high-risk (International Neuroblastoma Risk Group). Seven patients had relapsed before IREC. One patient (2%) showed partial response and 37 patients (86%) developed stable disease (disease control rate: 88%). Grade IV neutropenia was observed in 127 cycles (97%), while ≥ grade III gastrointestinal toxicity was observed in 3 cycles (2%). There was no IREC-related mortality. The one-year overall survival and progression-free survival rates were 65% and 52%, respectively. Patients with UGT1A1 polymorphisms showed a higher frequency of grade IV neutropenia; however, there was no increase in treatment-related mortality or nonhematological toxicity in these patients. Patients with UGT1A1 gene polymorphisms showed better one-year survival rate than the wild type (80% vs. 44%, p = 0.012). Conclusions: This study suggests that IREC is well-tolerated by patients with UGT1A1 polymorphisms and is a promising second-line chemotherapy for refractory/relapsed neuroblastoma.