Randomized trials suggest improved disease-free survival in low-grade non-Hodgkin's lymphoma (LGNHL) when interferon is combined with multiagent chemotherapy. This phase II trial was conducted to investigate the feasibility of combining fludarabine monophosphate (fludarabine) and IFN in a regimen for treatment of LGNHL. Twenty-one patients were evaluable. Median age was 55 years, and patients had been treated with an average of 1.7 chemotherapy regimens before enrollment. Patients received 25 mg/m2 of fludarabine intravenously on days 1 through 5 followed by 2 x 10(6) U/m2 of interferon-alpha-2a subcutaneously on days 22 through 26. Cycles were repeated every 4 weeks with delays and dose modifications for significant cytopenias. Patients were restaged after cycles 4 and 8, and those with at least a partial response to therapy were given maintenance therapy consisting of 2 x 10(6) U/m2 interferon-alpha-2a subcutaneously three times per week for 6 months. The overall response rate was 76% with a 25% complete response (CR) rate. Overall response rates were 75% (3/4 with 2 CR's) for chemotherapy-naive patients and 76% (13/17 with 3 CR's) for previously treated patients. Median time to progression was 12 months, and currently two patients are without evidence of progression at a median follow-up of 55 months. Grade III or greater toxicities included neutropenia (39%), anemia (17%), thrombocytopenia (5%), fevers/chills (5%), and fatigue (5%). Fludarabine and interferon can be effectively and safely combined in a regimen with significant activity against LGNHL. A modification of this regimen may be suitable for further study.