Benign hematologic diseases are second only to trauma as the most common indication for splenectomy. Immune thrombocytopenic purpura (ITP) is the most common indication for splenectomy and comprises greater than 70% of patients undergoing splenectomy for benign disease. Additional benign hematologic conditions that are indications for splenectomy include patients with congenital hemolytic anemia; metabolism abnormalities; hemoglobinopathies and erythrocyte structure abnormalities (e.g., hereditary spherocytosis and elliptocytosis).

Splenectomy may be indicated as a diagnostic tool or for palliation in patients with malignant hematologic disease. Surgical staging is utilized most often in Hodgkin's disease, resulting in a change in diagnosis and subsequent impact on therapy and prognosis in up to 30–40% of patients. Splenectomy can also provide relief to patients with symptomatic splenomegaly, which may or may not be accompanied by hypersplenism. Patients with malignant hematologic diseases are more likely to have massively enlarged spleens (> 1,000 g), resulting in significant discomfort and pain as well as early satiety. When splenomegaly is accompanied by cytopenias (hypersplenism), the cytopenia often improves or sometimes is even cured by removal of the spleen.