Etoposide produces reversible inhibition of topoisomerase II, leading to cleavage of DNA, and thereby has an antitumor effect. This mechanism suggests that the longer treatment is continued, the greater the antitumor effect will be. In the present study, both therapeutic and adverse effects of long-term treatment with low-dose oral etoposide were studied in 29 patients aged greater than or equal to 65 years with non-Hodgkin's lymphoma (NHL) for whom standard chemotherapy was not effective or refractory. These patients received etoposide at a dose of 50 mg/d for as long as possible. Treatment was continued until white blood cell count decreased to less than or equal to 2,000/mu L or the platelet count decreased to less than or equal to 5 x 10(4)/mu L. According to the World Health Organization (WHO) criteria of therapeutic effects, 6 (20.7%) of the 29 patients achieved complete remission and 13 patients (44.8%) had partial remission, for a response rate of 65.5%. Adverse effects of greater than or equal to grade 3 included leukopenia in 24 patients (82.8%) and anemia in 7 (24.1%). Granulocyte colony-stimulating factor (GCSF) was given in combination with etoposide to eight patients because of leukopenia (granulocyte count less than or equal to 1,000/mu L). In view of the excellent subjective tolerance, low incidence of serious adverse effects, and good activity, single agent oral etoposide given continuously over prolonged periods represents a useful treatment for elderly patients with NHL.