Marginal zone cell lymphoma is a recently described entity among the non-Hodgkin's lymphomas. It likely originates from the marginal zone B cells in the spleen and equivalent cells in the lymph node and extranodal tissues. Recent evidence indicates that marginal zone B cells are functionally heterogeneous and may differ with respect to the pattern of somatic hypermutation in their Ig variable genes. To test whether marginal zone lymphomas may originate from different subsets of marginal zone B cells, we performed a sequence and mutation analysis of the rearranged Ig heavy chain (IgH) variable genes (VH) of a series of 14 cases of marginal zone lymphoma, occurring in the spleen (4), the lymph node (4), the stomach (2), the orbit (2), the tongue (1), and the skin (1). Our data show that marginal zone cell lymphomas preferentially rearrange the VH4, VH3, and VH1 family genes, without preference for any particular VH gene. Somatic mutations are present in 13 cases; one case of marginal zone cell lymphoma of the skin showed a germline configuration of the rearranged VH gene. Mutation analysis shows evidence of antigen selection in three cases of marginal zone cell lymphoma, one of the spleen, stomach, and orbit, respectively. No evidence of antigen selection was present in the other cases. These data indicate that marginal zone cell lymphomas may arise from different subsets of marginal zone B cells. In addition, lymphomagenesis may not be triggered by antigen in all cases of marginal zone cell lymphoma.