Cellular immunophenotypic studies were performed on a cohort of randomly selected IgM⁺ B-chronic lymphocytic leukemia (B-CLL) cases for which Ig V_H and V_L gene sequences were available. The cases were categorized based on V gene mutation status and CD38 expression and analyzed for treatment history and survival. The B-CLL cases could be divided into 2 groups. Those patients with unmutated V genes displayed higher percentages of CD38⁺ B-CLL cells (≥30%) than those with mutated V genes that had lower percentages of CD38⁺ cells (<30%). Patients in both the unmutated and the ≥30% CD38⁺ groups responded poorly to continuous multiregimen chemotherapy (including fludarabine) and had shorter survival. In contrast, the mutated and the <30% CD38⁺ groups required minimal or no chemotherapy and had prolonged survival. These observations were true also for those patients who stratified to the Rai intermediate risk category. In the mutated and the <30% CD38⁺ groups, males and females were virtually equally distributed, whereas in the unmutated and the ≥30% CD38⁺ groups, a marked male predominance was found. Thus, Ig V gene mutation status and the percentages of CD38⁺B-CLL cells appear to be accurate predictors of clinical outcome in B-CLL patients. These parameters, especially CD38 expression that can be analyzed conveniently in most clinical laboratories, should be valuable adjuncts to the present staging systems for predicting the clinical course in individual B-CLL cases. Future evaluations of new therapeutic strategies and drugs should take into account the different natural histories of patients categorized in these manners.