PURPOSE: To compare response rates for two schedules of irinotecan with vincristine in patients with rhabdomyosarcoma at first relapse or disease progression. PATIENTS AND METHODS: Patients with first relapse or progression of rhabdomyosarcoma and an unfavorable prognosis were randomly assigned to one of two treatment schedules of irinotecan with vincristine: regimen 1A included irinotecan 20 mg/m(2)/d intravenously for 5 days at weeks 1, 2, 4, and 5 with vincristine 1.5 mg/m(2) administered intravenously on day 1 of weeks 1, 2, 4, and 5; regimen 1B included irinotecan 50 mg/m(2)/d intravenously for 5 days at weeks 1 and 4 with vincristine as in regimen 1A. Disease response was assessed at week 6. Those with responsive disease continued to receive 44 weeks of multiagent chemotherapy that incorporated the assigned irinotecan-vincristine regimen. RESULTS: Ninety-two eligible patients were randomly assigned (1A, 45; 1B, 47). Response could be assessed in 89 patients (1A, 42; 1B, 47). There were five complete responses and six partial responses on regimen 1A (response rate, 26%; 95% CI, 16% to 42%) and 17 partial responses on regimen 1B (response rate, 37%; 95% CI, 25% to 51%; P = .36). Neutropenia was less common on regimen 1A (P = .04). One-year failure-free and overall survival rates for regimen 1A were 37% (95% CI, 23% to 51%) and 55% (95% CI, 39% to 69%), respectively, and for 1B, they were 38% (95% CI, 25% to 53%) and 60% (95% CI, 44% to 72%). CONCLUSION: There was no difference in the response rates between the two irinotecan-vincristine schedules. We recommend the shorter, more convenient regimen (1B) for further investigation.