Splenic marginal zone lymphomas (SMZLs) have been proposed to originate from postgerminal center memory B cells that usually have mutated immunoglobulin heavy-chain variable (VH) genes. However, the majority of SMZLs are thought to express both IgD and IgM, which is more typical of naïve B cells that have unmutated VH genes. To better define the SMZL cell of origin and pathogenesis, we studied the histological and immunophenotypic features of eight cases and also sequenced their rearranged VH genes. Half of the cases had unmutated VH genes consistent with a naïve B-cell origin and half had mutated VH genes consistent with a memory B-cell origin. Most of the unmutated cases (three of four) were positive for IgD, which further supports a naïve B-cell origin, whereas the others were negative. In addition, VH gene segment use seems to be nonrandom because seven of eight cases used genes from the VH1 or VH4 families and repetitive use of the V1-2, V1-69, and V4-34 gene segments was observed. Our results suggest there are two types of SMZLs, one that originates from naïve marginal zone B cells in addition to one that originates from memory marginal zone B cells, and that antigen selection may be occurring during lymphomagenesis.