The mutational status of the variable region of the immunoglobulin heavy chain gene (IgV_H) is an important prognostic marker in B‐cell chronic lymphocytic leukaemia (B‐CLL), with mutated patients having improved outcome. To examine the impact of mutational status on V_H, D_H, and J_H gene segment location and immunogenicity, we analysed 375 IgH sequences from 356 patients with B‐CLL. Although V_H and D_H gene usage was different in mutated compared to unmutated patients, there was no impact of gene location on frequency of use or clinical outcome. Surprisingly, somatic mutations did not increase the immunogenicity of the Ig, as assessed by predicted binding affinity of Ig‐derived peptides to major histocompatibility Class I and Class II molecules. Even excluding patients using V_H1‐69, cases using the V_H1 gene family had a poor outcome. Both mutated and unmutated CLL patients demonstrated evidence of antigen selection. The worst outcome was seen in the subset of 14 unmutated patients with similar HCDR3 amino acid sequence using V_H1‐69, D_H3‐3 and J_H6, suggesting an antigen‐driven process modulating the clinical course.