Mantle cell lymphoma (MCL) is believed to originate from a naive B cell. However, we recently demonstrated that a subset of MCL displayed mutated V_H genes. We also reported restricted use of certain V_H genes. To assess the prognostic impact of these new findings, we performed V_H gene analysis of 110 patients, revealing that 18 (16%) patients had mutated and 92 (84%) patients had unmutated V_H genes. Because the mutation rate was low in the mutated group (2.2%-6.7%), further investigation of the germline V_H gene in T cells from 5 patients with mutated V_H genes was carried out; results showed that the unrearranged V_H gene was identical to the published sequence. These data confirm that the base pair substitutions within the rearranged V_H genes represent hypermutations, and indicate germinal center exposure. However, V_H gene mutation status did not correlate with prognosis because there was no difference in clinical outcome between the unmutated and mutated groups. The most frequently used V_H genes were V_H3-21 (21 patients) and V_H4-34 (19 patients). A novel finding was that V_H3-21⁺ MCL almost exclusively expressed λ light chains and displayed highly restricted use of the V_λ3-19 gene. V_H3-21⁺patients had longer median survival than the remaining patients (53 vs 34 months; P = .03), but they tended to be younger at diagnosis. The combined use of V_H3-21/V_λ3-19 suggests a possible role for antigen(s) in the pathogenesis of these tumors and indicates that V_H3-21⁺ patients constitute a new MCL entity.