The importance of schedule in the cytotoxic efficacy of etoposide is supported by an increasing amount of clinical data. We studied the efficacy of oral etoposide (50 mg/m2/d x 21 repeated every 28 to 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%) had partial responses, including five of nine 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. Two patients responded to chronic oral etoposide immediately after disease progression with intravenous etoposide-containing regimens, demonstrating the improved efficacy of the chronic schedule. Single-agent oral etoposide, administered at 50 mg/m2/d for 21 days, provides an effective and convenient treatment option for patients with indolent lymphoma. Incorporation of this schedule into combination regimens for aggressive lymphoma is currently under investigation. In addition, we are exploring schedule modifications that may further decrease toxicity while maintaining efficacy.