Ten patients with diffuse large cell (histiocytic) lymphoma of the spleen had a characteristic clinical presentation and pathologic findings. Patients presented with left upper quadrant pain, fever, weight loss, and an elevated sedimentation rate. Imaging studies revealed an enlarged spleen with a discrete mass in all cases. Moderate to massive splenomegaly (average weight, 1025 g) was found at laparotomy; a single large mass or multiple confluent nodules with extensive central necrosis replaced 85% to 90% of the parenchyma. The tumor transgressed the splenic capsule in nine of ten cases, and either invaded or was adherent to the diaphragm, stomach, pancreas, or abdominal wall. Lymph nodes in the splenic hilum or retroperitoneum were frequently involved. Seven patients were in Ann Arbor Stage II, and three were in Stage I. Eight of the ten lymphomas were subclassified as centroblastic (large noncleaved cell) and two were immunoblastic. The B-cell lineage of six tumors was established by the presence of monoclonal immunoglobulin. Despite combination chemotherapy, with or without radiation, three of the seven patients whose follow-up was adequate died in less than 2 years; four are alive at 7, 12, 12, and 81 months, respectively, the last two with recurrent lymphoma. Large cell lymphoma of the spleen is a likely diagnosis in patients who present with left upper quadrant pain, fever, and radiographic evidence of a splenic mass.