We assessed the efficacy and toxicity of alternating non-cross-resistant chemotherapy in the treatment of advanced NSCLC. Cycles of cisplatin, methotrexate, doxorubicin, and cyclo-phosphamide were alternated monthly with cisplatin and etoposide. Patients had measurable disease, ECOG performance status 0–3, no previous chemotherapy, and stage II (inoperable). III, or IV disease without brain metastases. Between 1988 and 1990, 28 patients were entered in the study: 20 patients (71%) had stage IV disease, 19 (68%) were evaluable for response and toxicity; 4 (21%) responded. There were 3 partial respondcrs (16%) and 1 complete responder (5%). The mean duration of response was 60.5 weeks (range: 32–105+ weeks), and the median time to progression was 12 weeks (range: 8–105+ weeks). The median survival time for all 28 patients was 24 weeks (range: 3–153+ weeks). The most significant toxicity was grade 3–4 leukopenia experienced by 63% of patients, but there were no episodes of sepsis and no treatment-related deaths. This regimen of alternating cycles of cisplatin-containing chemotherapy is safe, but its efficacy is not superior to other combination chemotherapy regimens.