Monocytoid B-cell lymphoma, low-grade B-cell lymphoma of mucosa-associated lymphoid tissue, and primary splenic marginal zone cell lymphoma (SMZCL) were originally described as distinct clinicopathologic entities. On the basis of morphologic and immunologic similarities, monocytoid B-cell lymphoma and lymphoma of mucosa-associated lymphoid tissue recently have been grouped together as nodal and extranodal types of marginal zone B-cell lymphomas (MZBCLs) in the Revised European-American Classification of Lymphoid Neoplasms. Primary SMZCL, although related, is considered a separate provisional entity. Trisomies 3, 7, and 12 are common in non-Hodgkin's lymphomas. Several recent studies reported that MZBCLs arising in sites of mucosa-associated lymphoid tissue have a high frequency of trisomy 3. To assess whether similar numerical cytogenetic abnormalities are present in MZBCLs with prominent monocytoid B-cell cytologic features, we performed a retrospective study, using formalin-fixed, paraffin-embedded tissue blocks from 36 cases. By use of fluorescence in situ hybridization to detect chromosome trisomies, we identified trisomy 3 in 11 (85%) of 13 extranodal MZBCLs with monocytoid B cells (MZBCL-Es), in 6 (50%) of 12 nodal MZBCLs of monocytoid B-cell type (MZBCL-Ns), but in only 2 (18%) of 11 SMZCLs. Trisomies 7 and 12 were found at lower frequencies. These data suggest that trisomy 3 is a common numerical chromosomal abnormality of MZBCL-Es and MZBCL-Ns with monocytoid B-cell features. Despite similar morphologic and immunophenotypic characteristics, the low incidence of trisomy 3 in the SMZCL cases implies that this process may be genetically distinct.