The authors examined the relationship between CD5 antigen expression and a nodal or extranodal presentation for three subtypes of low-grade non-Hodgkin's lymphoma: small lymphocytic (23 cases), small lymphocytic with plasmacytoid differentiation (10 cases), and lymphocytic lymphoma of intermediate differentiation (IDL) (29 cases). Antigen expression was studied by the avidin-biotin complex immunoperoxidase technique in frozen sections and correlated with expression of other B- and T-cell markers. Lack of CD5 expression was significantly associated with extranodal presentation among the over-all study group (p less than 0.001), as well as for those with small lymphocytic lymphoma and IDL, but not for those presenting with small lymphocytic lymphomas with plasmacytoid differentiation (p less than 0.21). Eleven patients presented exclusively with extranodal disease involving lung and respiratory tract, skin and subcutaneous tissue, salivary gland, stomach, conjunctiva, and uterus. All such lesions were CD5 negative and had been classified as small lymphocytic (four cases), small lymphocytic-plasmacytoid (four cases), and IDL (three cases). Retrospective review of these 11 cases demonstrated common histologic features described as characteristic of lymphomas of mucosa-associated lymphoid tissue (MALT). Two additional patients presented with disseminated nodal disease and involvement of gastrointestinal tract and oropharynx; both were CD5 positive. These findings support the concept that at least two antigenically distinct B-cell subpopulations may be involved in pathogenesis of low-grade small lymphocytic malignancies.