We report a case of aggressive non-Hodgkin's lymphoma of the small cell type arising in the small intestine and having a natural killer cell phenotype. Immunophenotyping of frozen tissue sections revealed a lack of reactivity with the pan-T-cell markers CD3 and CD5, and no reaction with B-cell markers. Positive staining was obtained with antibodies to CD2, CD7, and CD56. Molecular studies were negative for clonal T gamma, T beta and immunoglobulin heavy-chain gene rearrangements. Natural-killer-cell-associated cytotoxin was demonstrated by positive staining with an antibody to perforin, a protein present in the granules of large granular lymphocytes. Despite its indolent histologic appearance, the aggressive nature of this neoplasm was suggested by the expression of the activation markers CD38 and CD71, and the nuclear proliferation marker Ki67, and confirmed clinically by its rapid recurrence with extensive involvement of the pelvic organs, resistance to chemotherapy, and the short survival of the patient. Distinct from many Asian cases, Epstein-Barr virus genome was not detectable in the tumor. This case emphasizes the importance of recognizing non-Hodgkin's lymphomas with a natural killer cell phenotype as a distinct entity, both biologically and clinically.