Seventeen patients with small-cell lung cancer refractory to combination chemotherapy were entered in a study of VP-16 and infusional Ara-C. All patients were evaluable for response and 14 were evaluable for toxicity (three deaths that occurred after the first cycle of therapy were due to progressive tumor, and toxicity could not be evaluated in these three patients). Ara-C was given as a continuous intravenous infusion of 45 mg/m2/day for 72 h; VP-16 was given as three daily intravenous bolus doses of 50 mg/m2 at hours 12, 36, and 50 of the 72-h Ara-C infusion. Because of excessive myelotoxicity in the first six patients, the last 11 patients began treatment at a lower dose of Ara-C, 25 mg/m2/day. Six of 17 patients had previously been exposed to VP-16 as part of their initial chemotherapy regimen. The 17 patients received 32 cycles of therapy. Myelotoxicity was severe, with nadir granulocyte counts less than 500/microliters or platelet counts less than 30,000/microliters in four treatment cycles (including two at the lower Ara-C dose). No patient experienced an objective response to this therapy. We conclude that the combination of VP-16 and infusional Ara-C at these doses is excessively toxic and does not warrant further investigation in refractory small-cell lung cancer.