The authors studied 56 cases of diffuse low-grade B-cell lymphoma using frozen tissue sections and a large panel of monoclonal antibodies that distinguish subsets of normal B cells. They compared the immunophenotypes with the histologic subtypes defined by the Rappaport classification, Working Formulation, and Kiel classification to correlate antigen expression with the morphologic subtypes defined in these classification schemes and to define the contribution of immunophenotype to clinically relevant subclassification. All categories in all classifications showed some heterogeneity of antigen expression; however, antigen expression correlated better with four major subgroups defined by the Kiel classification: (1) CD5+ CD10– CD23+ CD43+: chronic lymphocytic leukemia (CLL); (2) CD5+ CD10–/+ CD23– CD43+: centrocyte (mantle cell) lymphoma; (3) CD5– CD10+/– CD23–/+ CD43–: centroblastic/centrocytic (CB/CC) lymphoma; and (4) CD5–CD10– CD23–/+ CD43–/+: immunocytoma, mucosa-associated lymphoid tissue (MALT)-type, and monocytoid B-cell lymphoma. These subgroups had distinctive clinical features. Patients with centrocytic lymphoma were predominantly male (5.5:1) and had a significantly worse probability of survival than those with either CLL or MALTtype lymphoma (P = 0.001). The group with CB/CC lymphoma had an equal male–female ratio and an intermediate prognosis. Most patients with MALT-type and nodal monocytoid B-cell lymphomas were female (2:1); the disease-free survival for patients with extranodal MALTtype lymphoma was significantly better than that for all patients with other lymphoma subtypes except CB/CC (P < 0.01). The group with non-MALT immunocytoma had a slight male predominance, a high frequency of monoclonal gammopathy, and an intermediate prognosis. In differential diagnosis, CD23 was useful in distinguishing B-cell CLL from centrocytic lymphoma (P < 0.0001); CD5 (P < 0.0001), CD6 (P < 0.005), and CD43 {P < 0.0001) distinguish centrocytic lymphoma from CB/CC lymphoma; and CD 10 (P < 0.005), CD43 (P = 0.06), Leu-8 (P = 0.08), and Ig heavy chain (P = 0.01) may help distinguish CB/CC lymphoma from immunocytoma, monocytoid B-cell lymphoma, and MALT-type lymphoma. Differences in antigen expression and clinical features among these Kiel classification subgroups suggest that they represent distinct biologic entities. The Working Formulation categories do not delineate these diseases clearly.