Prolonged remission can now be induced in the majority of patients with advanced Hodgkin's disease (HD) by the use of non-cross-resistant regimens. The aim of this retrospective analysis was to evaluate the efficacy and tolerability of a hybrid chemotherapy regimen (ChlVPP/ABV-VP16) in this unfavorable subset of patients. From 1982 to 1997 thirty-six previously untreated patients with advanced HD, Stages IIB to IV according to the Ann Arbor classification, were treated with the ChlVPP/ABV-VP16 regimen. The median age of the group was 29 years (range, 18 to 74), and 50% of them had bulky disease. Complete remission (CR) was induced in 31 patients (86%); 3 patients achieved partial responses and 2 had progressive disease. The median follow-up duration is 5.7 years, with a 5-year overall survival rate of 80%. At 5 years, the time to progression (TTP) and event-free survival (EFS) were 71% and 64%, respectively. Acute toxicity was quite acceptable, and there were no treatment-related deaths. A total of 3 second malignancies (8%) were documented. In conclusion, the ChlVPP/ABV-VP16 hybrid is an active regimen for use in advanced HD. Its overall survival, TTP and CR rates make this regimen an attractive alternative to MOPP/ABVD. However, the possibility of the development of second tumors is worrisome, although the relatively brief interval between the end of treatment and tumor detection may imply caution about the possible relationship.