Splenomegaly was studied retrospectively at the University of California, San Francisco, School of Medicine, on all patients (N = 2,056) for the years 1913 to 1962. The patients were classified into several diagnostic groups, and these groups were tested for statistical significance (chi(2)) with many clinical and laboratory variables to determine their predictive value. Hematologic disorders were associated with 57% of cases of splenomegaly and 81% of cases of massive splenomegaly. Among patients with splenomegaly, 19% had infectious diseases, 11% had hepatic diseases, and 9% had congestive or inflammatory disorders. The residual 4% were considered to have primary splenic disorders or a disorder of unknown cause. The commonest diseases associated with splenomegaly were hematologic (acute and chronic leukemias), infectious (malaria, endocarditis, and tuberculosis), hepatic (chronic liver disease), congestive (congestive heart failure), inflammatory (thyrotoxicosis), and other (cancers not metastatic to the spleen). The diseases most frequently associated with massive splenomegaly were the chronic leukemias. The disease with the highest incidence of massive splenomegaly was myelofibrosis (23 of 29 patients, 78%). Splenectomy was performed in 154 patients (7%), primarily for hematologic amelioration and hepatic hypersplenism. Hematologic diseases showed significant associations with lymphadenopathy, generalized lymphadenopathy, massive splenomegaly, and cytoses (P .001) and with progressive splenic enlargement (P < .02). Infectious diseases showed significant association with fever, and hepatic diseases showed significant association with abnormal results of liver function tests (P < .001). The findings of this retrospective study should be validated prospectively.