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Background: Splenectomy is commonly used to treat refractory immune–mediated cytopenia, but there are no established factors that are associated with response to the procedure. Objectives: A cohort study was conducted to evaluate the hematologic and surgical outcomes of splenectomy in adult patients with immune cytopenias and identify preoperative factors associated with response. Methods: Data from the Cleveland Clinic Foundation for 1824 patients aged over 18 who underwent splenectomy from 2002 to 2020 were analyzed. Results: The study found that the most common indications for splenectomy were immune thrombocytopenic purpura (ITP) and autoimmune hemolytic anemia, with a median age of 55 years and median time from diagnosis to splenectomy of 11 months. Hematologic response rates were 74% overall, with relapse in 12% of cases. Postsplenectomy discordant diagnoses were present in 13% of patients, associated with higher relapse rates. Surgery‐related complications occurred in 12% of cases, whereas only 3% of patients died from disease complications. On univariate analysis, preoperative factors associated with splenectomy treatment failure were ≥3 lines of pharmacologic treatment, whereas isolated thrombocytopenia, primary ITP, and age ≤40 years had a strong association with response. The multivariable regression confirmed that treatment failure with multiple lines of medical therapy was associated with the failure to respond to splenectomy. Conclusion: Overall, the study demonstrates that splenectomy is an effective treatment option for immune‐mediated cytopenias with a low complication rate. [ABSTRACT FROM AUTHOR]