Eight-eight previously untreated patients with small cell lung cancer were treated with a combination of VP16, adriamycin and vincristine (VPAV) for three courses. Resistance to these drugs is associated with the multidrug resistance (MDR) membrane glycoprotein in cell lines in vitro. The clinical relevance of this mechanism of resistance was assessed by using a second line treatment with intravenous infusions of ifosfamide/mesna 5 g/m2 every 3 weeks in patients with only partial responses or non-responders. Cross-resistance to alkylating agents is rare in the MDR. Ifosfamide produced partial responses in six (43%) of 14 patients unresponsive to prior therapy. Intravenously infused ifosfamide/mesna was also used in consolidation therapy with only minor bone marrow or urinary tract toxicity. This did not prevent CNS relapse. The overall response rate to VPAV was 69% and for all treatment modalities, 75%. Median survival for all patients ws 39.5 weeks and 59 weeks for all patients attaining complete response. The addition of large fraction chest irradiation given with the final course of induction chemotherapy to those with good chemotherapy responses produced a further response in 44% of assessable patients. Combined modality treatment resulted in moderate and reversible toxicity. The lack of improved survival with ifosfamide and the resistance of the majority of patients to salvage with ifosfamide/mesna suggested that the MDR is not the major mechanism of resistance in the clinic, since cross-resistance to alkylating agents of this type is not a feature of MDR cells.