In an attempt to circumvent innate or acquired tumor-cell resistance to chemotherapy, patients with small-cell lung cancer (SCLC) were treated with induction therapy that incorporated two active and potentially non-cross-resistant chemotherapy regimens on two National Cancer Institute of Canada (NCI-C) trials. Patients with limited disease (LD) SCLC were treated with cyclophosphamide, doxorubicin (Adriamycin [Adria Laboratories, Columbus, Ohio]) and vincristine (CAV) and VP-16 plus cisplatin in two different sequences. One arm was randomized to receive CAV alternating with VP-16 plus cisplatin for a total of six treatment cycles, and the other arm received three courses of CAV followed by three courses of VP-16 plus cisplatin. Both treatment strategies produced similar response rates and survival curves, and each treatment group has a projected 2-year survival of 20%. Patients with extensive disease (ED) were treated with either six cycles of CAV (standard regimen) or CAV alternating with VP-16 plus cisplatin for a total of six treatment cycles. In this study, the alternating regimen produced a higher complete response (CR) rate (40% v 27%) and overall response rate (61% v 39%; P less than .01). The progression-free survival was also superior for the alternating arm (P = .001), as was overall survival (P less than .05). The frequency of thrombocytopenia and severe gastrointestinal toxicity was slightly greater in the alternating arm, but the frequency of neutropenia and infection was less. The alternation of CAV and VP-16 plus cisplatin during induction therapy is an effective treatment strategy in the management of SCLC and superior to CAV alone in extensive SCLC.