To evaluate the response rate and potential toxicities, a phase II trial was conducted of fludarabine and cyclophosphamide with filgrastim support in patients with previously untreated low-grade and select intermediate-grade lymphoid malignancies. Symptomatic patients with preserved end organ function received cyclophosphamide 600 mg/m(2) intravenous (iv) day 1 and fludarabine 20 mg/m(2) iv days1 through 5, followed by filgrastim 5 microg/kg subcutaneous starting approximately day 8. Treatment was repeated every 28 days until maximum response or a maximum of 6 cycles. Sixty patients, median age 53.5 years, were enrolled. Thirty-seven patients with non-Hodgkin lymphoma (NHL) were stage IV and 6 were stage III. Eleven of 17 patients with chronic lymphocytic leukemia (CLL) were Rai intermediate risk and 6 were high risk. The overall complete response (CR) rate was 51% and the partial response (PR) rate was 41%. Of patients with CLL, 47% achieved a CR and the remaining 53% achieved a PR. Of patients with follicular lymphoma, 60% achieved CR and 32% achieved a PR. Although the toxicity of this regimen was mainly hematologic, significant nonhematologic toxicities, including infections, were seen. Twenty-four patients subsequently received an autologous or allogeneic stem cell transplant. Engraftment was rapid, and there were no noticeable procedure toxicities in the immediate posttransplant period attributable to the fludarabine and cyclophosphamide regimen. Fludarabine, cyclophosphamide, and filgrastim make up a highly active and well-tolerated regimen in CLL and NHL.