Fludarabine is an active agent in low-grade non-Hodgkin's lymphoma and chronic lymphocytic leukemia. Paclitaxel is also active in patients with refractory lymphoma, and preclinical data suggest an additive effect with fludarabine in vitro. We performed a phase I trial of fludarabine (25 mg/m(2) d 1-3) plus a 3-h infusion of paclitaxel (125, 150, or 175 mg/m(2)) on d 3 every 28 d in 13 patients with non-Hodgkin's lymphoma. The paclitaxel dose was escalated in cohorts of 3-4 patients using standard phase I design schema. Dose-limiting toxicity was defined as febrile neutropenia, platelet nadir less than 50,000/microL, or grade 3-4 nonhematologic toxicity. Thirteen patients were accrued to the study, 8 of these 13 patients (62%) had received prior chemotherapy. At the 125-, 150-, and 175-mg/m(2) dose levels of paclitaxel, dose-limiting toxicity occurred in 1/4, 0/4, and 0/4 patients, respectively. The single patient with dose-limiting toxicity had febrile neutropenia. Partial response occurred in two of eight patients with low-grade lymphoma and none of five patients with other types of lymphoma. A paclitaxel dose of 175 mg/m(2) given as a 3-h infusion on d 3 in conjunction with fludarabine (25 mg/m(2) d 1-3 every 4 wk) is a well-tolerated regimen for non-Hodgkin's lymphoma. Further study will be required in order to determine whether the fludarabine paclitaxel is more active than fludarabine alone in patients with low-grade lymphoma and chronic lymphocytic leukemia