In the studies described here, 40 extranodal lymphoid tumors obtained from 38 patients were evaluated by cell-marker analysis and the results correlated with the light microscopic features. These infiltrates were investigated for the present composition of cells expressing Ia antigens, surface immunoglobulin (SIg), including kappa and lambda light chains, sheep erythrocyte (E) rosette formation, and acid a-naphthyl acetate esterase (ANAE) activity. Fifteen biopsy specimens consisted of variable proportions of benign T and polyclonal B cells; these 15 lesions had the histopathologic features of benign pseudolymphomas. The remaining biopsy specimens consisted almost entirely of B cells bearing monoclonal SIg (18 cases) or a great preponderance of T cells (five cases) or non-B, non-T (null) cells (two cases); these 25 lesions were classified histopathologically as malignant lymphomas. Thus, the extranodal lymphoid infiltrates were divisible, according to their cell-marker characteristics, into two categories: lesions that are immunologically polyclonal and lesions that are immunologically monoclonal B-cell proliferations or consist of a great preponderance of T or null cells. In each case, polyclonality correlated with benign cytomorphologic features and monoclonality correlated with malignant histopathology. Cell-marker analysis appears to represent an important adjunct to light microscopy in distinguishing histologically problematic benign pseudolymphomas from malignant lymphomas that arise in the extranodal tissues. Cell marker analysis will undoubtedly provide insights into the histogenesis, natural history, and biologic behavior of the extranodal lymphoid neoplasms not attainable using light microscopy alone.