Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) typically involves nodal or extranodal tissues as a diffuse proliferation with pseudofollicular growth centers obliterating normal architecture. We describe 16 cases of CLL/SLL in which the neoplasm was confined to the marginal zone, perifollicular, or interfollicular regions surrounding benign lymphoid follicles in either nodal or extranodal sites. Twelve of 12 (100%) patients with adequate staging data had disseminated disease (Stage III or IV) at presentation. Eight of the 16 (50%) patients had absolute peripheral lymphocytosis (range, 5 to 30 x 10(9)/L). Pseudofollicular growth centers were identified in 14 of 16 cases (87.5%). Immunophenotypic studies revealed that the tumor cells were positive for CD20 (16/16) and CD5 (11/11) in all cases examined. CD23 was positive in 12 of 14 (86%) interpretable cases. IgM and IgD were positive in 13 of 14 (93%) and 10 of 10 (100%) interpretable cases, respectively. All cases were negative for CD3 (16/16), CD45RO (16/16), CD10 (15/15), and cyclin D1 (15/15). We conclude that CLL/SLL can have unusual patterns of involvement, including marginal zone, perifollicular, and interfollicular patterns that can be difficult to recognize histologically. Thirteen of 16 (81%) cases in this study were misinterpreted by the referring pathologists. Recognition of proliferation centers coupled with demonstration of a CD5+ CD23+ B-cell immunophenotype establishes the correct diagnosis of CLL/SLL.