S urvival of patients with B cell chronic lymphocytic leukemia (B-CLL) can be predicted by analysis of mutations in the immunoglobulin heavy chain variable gene (IGHV). Patients without mutations (unmutated [UM]) are at greater risk for disease progression and death than patients with mutations (M). Despite this broad prognostic difference, there remains wide intragroup variation in the clinical outcome of UM patients, especially those with low/intermediate Rai risk disease. We evaluated UM B-CLL patients with low/intermediate Rai risk to determine the relationship between IGHV, IGH diversity (IGHD), and IGH joining (IGHJ) gene usage and time to treatment (TTT). Irrespective of IGHV usage, UM patients whose B-CLL cells expressed the IGHD3-3 gene had a significantly shorter TTT than other UM B-CLL patients, and specifically, use of the IGHD3-3 gene in reading frame 2 (RF2) predicted shorter TTT. As expected, Rai risk was the best single prognostic factor for TTT; however, IGHD usage was also a significant variable for TTT. Therefore, both IGHD gene and IGHD RF usage have prognostic relevance in UM B-CLL patients with low/intermediate Rai risk disease. In addition, these data support the concept that antigen-driven selection of specific Ig receptors plays a role in the clinical course of B-CLL.