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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 …