In chronic lymphocytic leukemia (CLL), biologic risk factors such as immunoglobulin variable heavy chain gene (V_H) mutation status, CD38 expression level, and genomic aberrations have recently been identified, but the relative prognostic impact of the individual parameters is unknown. In the current study, we analyzed V_H mutation status by polymerase chain reaction and sequencing (n = 300), genomic aberrations by fluorescence in situ hybridization (+3q, 6q−, +8q, 11q−, +12q, 13q−, t(14q), 17p−) (n = 300), and CD38 expression by triple-color FACS (CD5, CD19, CD38) (n = 157) in a unicentric CLL cohort. The prognostic influence of V_H mutation rate and CD38 expression level was tested by maximally selected log-rank statistics. A corrected P value (P_cor) for a cutoff level allowing the best separation of 2 subgroups with different survival probabilities was identified at 97% V_H homology (95% confidence interval [CI], 96%-98% homology,P_cor <.001) and at 7% CD38 expression (95% CI, 20%-71% expression, P_cor = .02). In univariate analyses, unmutated V_H genes and high CD38 expression levels predicted for shorter survival times. The overall incidence of genomic aberrations was similar in theV_H unmutated and V_Hmutated subgroups. High-risk genomic aberrations such as 17p− and 11q− occurred almost exclusively in the V_Hunmutated subgroup, whereas favorable aberrations such as 13q− and 13q− as single abnormalities were overrepresented in theV_H mutated subgroup. In multivariate analysis, unmutated V_H, 17p deletion, 11q deletion, age, WBC, and LDH were identified as independent prognostic factors, indicating a complementary role of V_H mutation status and genomic aberrations to predict outcome in CLL.