Based on the activity of fludarabine and doxorubicin in chronic lymphocytic leukemia (CLL), 30 patients received this combination. The median age of these patients was 61 years; median Zubrod performance status was one; median number of prior therapies was three; and median time to treatment was 53 months. Rai stage was 0 for two patients, I/II for 19 patients, and III/IV for nine patients. Prior treatment included fludarabine in 25 patients. In this regimen, fludarabine was administered as 30 mg/m2/d IV x 3 to 10 patients, 25 mg/m2/d IV x 4 to three patients, and to 17 patients as 30 mg/m2/d IV x 4. A 50 mg/m2 IV dose of doxorubicin was given to all patients. The first 17 patients received prednisone 30 mg/m2 x 5 days; however, this was discontinued due to other data demonstrating no therapeutic advantage and increased opportunistic infections when corticosteroids were added to fludarabine. Toxicity consisted primarily of infectious episodes: pneumonia nine, bacteremia one, FUO seven, and minor infection five. Two deaths from pneumonia occurred. Standard guidelines for response were used with the addition of a nodular CR group. Despite prior treatment with fludarabine in the majority of patients, the response rate in the 29 evaluable patients was CR 3%, nodular CR 17%, PR 35%, fail 38% and early death 7%. This combination of fludarabine and doxorubicin is active against CLL and warrants further study.