Sjogren's syndrome (SS) is frequently associated with both reactive and neoplastic lymphoproliferative disease. Over a 12-year period beginning in 1970, 21 of 138 patients with SS followed at two tertiary university medical centers had biopsies taken of enlarged lymph nodes (18) or extranodal lymphoid infiltrates (8). Many had immunologic studies performed on fresh tissue and all had paraffin-embedded tissue available for histochemical and immunoperoxidase studies. Eight of our patients had malignant lymphomas which were chiefly B cell neoplasms including two lymphoplasmacytic lymphomas and two follicular center cell lymphomas. The remaining 13 patients had either reactive adenitis (usually with follicular hyperplasia) or atypical lymphoid hyperplasia which failed to meet both histopathologic and immunopathologic criteria for malignancy. None of the nine patients with reactive hyperplasia has yet progressed to lymphoma, while one of four patients with atypical lymphoid hyperplasia progressed to overt lymphoma. Clinical features such as age, duration of disease, extent of lymphadenopathy, splenomegaly, or parotid swelling failed to identify those subsets of patients with lymphadenopathy at increased risk for lymphoma. Recognition of lymphoma in two patients was greatly facilitated by tissue immunologic studies demonstrating focal areas of monotypic B cell proliferation. In one patient in whom the histopathologic diagnosis was immunoblastic sarcoma of B cells, tumor cells were L26-negative and strongly UCHL1-positive suggesting T cell differentiation. In three patients with relatively homogeneous extranodal lymphoid infiltrates, B cell polyclonality on tissue immunoperoxidase studies, and the absence of cytologic atypia, precluded a diagnosis of malignant lymphoma; none of these three patients has progressed to overt lymphoma. Our results indicate that (1) patients with SS develop a variety of B cell lymphomas and other lymphoproliferative disorders, and (2) the nature of the lymphoproliferative disorder is best determined by multiparameter analysis including immunologic phenotyping.