The importance of schedule in the cytotoxic efficacy of etoposide is suggested by the mechanism of action and supported by clinical data in the treatment of small cell lung cancer. To further evaluate the effects of drug schedule, we studied the efficacy of oral etoposide SO mg/m2daily for 21 consecutive days, repeated every 28–35 days, in the treatment of refractory lymphoma. Twenty-five patients were treated; all had received previous chemotherapy and were considered incurable. Fifteen patients (60%) responded to treatment (14 partial responses, 1 complete response), including 5 of 9 patients who had received previous intravenous etoposide. Median response duration was 8 months in patients with low grade lymphoma and 3 months in those with intermediate or high grade lymphoma. The single complete responder remains disease-free 19 months after completion of therapy. Two patients responded to chronic oral etoposide immediately after progression on intravenous etoposide-contain-ing regimens, demonstrating improved efficacy of the chronic schedule. Single agent etoposide, administered at this dose for 21 days, provides an effective and convenient treatment option for patients with indolent lymphoma. Incorporation of this etoposide schedule into combination regimens for aggressive lymphoma is currently under investigation, and preliminary results are reported.We are currently conducting a phase I study using low dose, continuous infusion etoposide (25 mg/m2/day). By avoiding high peak serum levels and maintaining a constant serum level of approximately 1μg/ml, we hope to retain efficacy and minimize or avoid myelotoxicity. Continuous infusion was continued for as long as tolerated. Blood counts were measured weekly, and therapy temporarily interrupted if WBC<2000//μL developed. Six patients with previously treated lymphoma have been treated from 6–54 weeks. Myelosuppression was mild, and no other toxicity except alopecia was observed. Four of 6 responded to therapy. These preliminary data suggest that the toxicity of etoposide can be markedly altered and cytotoxicity can be retained using this method of administration.