Immunoglobulin variable heavy chain gene (V_H) mutation status and VDJ rearrangement structure were analyzed in 141 patients with mantle cell lymphoma (MCL) and correlated with biologic and clinical characteristics; 29% of the MCLs displayed mutated V_H using a 98% germline homology cutoff. Striking differences occurred in the V_H mutation subgroups with respect to the use of specific V genes. Rearrangements involving V4-34 and V3-21 were almost exclusively unmutated, whereas rearrangements using V4-59 and V3-23 were typically mutated. Significant association occurred between mutated V_H with shorter CDR3 lengths and the use of J_H4b. V3-21 and V4-59 were involved in highly characteristic rearrangements, implying that antigen specificity might have been involved in MCL development. There was no evidence for isotype switch recombination or Bcl-6 expression in any MCL. ZAP70 expression was not different in V_H-mutated or -unmutated MCL. Although the deletions 11q– and 17p– showed a balanced distribution, an overrepresentation was observed for trisomies +3q, +8q, and tetraploidy in the V_H-unmutated subgroup and +12q in the V_H-mutated subgroup. Clinically, mutated V_H was associated with a higher rate of complete remission, but there was no correlation between V_H mutation status and other clinical characteristics or overall survival.