Microvillous lymphomas (MVLs) are rare, poorly defined, large transformed cell lymphomas characterized by a cohesive sinus growth pattern and ultrastructural cytoplasmic processes. Most MVLs express B-cell antigens and have been compared ultrastructurally to transformed follicular center cells and follicular dendritic cells. For additional definition of the immunophenotype of these unusual B-cell lymphomas, we evaluated eight cases of MVL for B-cell-associated antigens (CD21, CD35, CDw75, DBA.44, bcl-2) using paraffin immunoperoxidase. CD56, the neural cell adhesion molecule, was tested because of the unusual, cohesive, sinus pattern of tumor cell growth seen in MVL. Molecular analysis for immunoglobulin heavy chain and bcl-2 gene rearrangements was performed to confirm B-cell clonality and to evaluate cases for possible follicular origin. All of the cases were marked as B cells (CD20 positive), and the clonal nature confirmed by immunoperoxidase in five cases (63%) of eight and polymerase chain reaction for immunoglobulin heavy chain in seven cases (88%) of eight. CDw75 staining was present in six cases and CD74 in seven. DBA.44 and CD21 and CD35 were negative in all of the cases, and four cases (50%) of eight expressed CD56. bcl-2 protein expression was seen in seven of eight cases; bcl-2 gene rearrangement was present in one case (33%) of three studied. In conclusion, MVLs are B-cell lymphomas demonstrating clonal immunoglobulin heavy chain gene rearrangement. The neoplastic cells express CDw75 and bcl-2 protein. The presence of bcl-2 rearrangements in a limited number of cases implies that at least some MVLs have a follicular origin. Fifty percent of MVLs express CD56, suggesting a role for adhesion molecules in the distribution of this lymphoma.