Background/Objectives: Splenectomy leads to a high rate of remission in chronic primary immune thrombocytopenia (ITP), but its unpredictable long-term positive outcomes and that it is a irreversible surgical approach discourage clinicians and patients. The identification of predictors of response may redefine the timing of splenectomy. In this retrospective, multicentric study we aimed to investigate clinical–histological predictors of splenectomy response in ITP patients and provide an easy-to-use score to predict splenectomy response in ITP. Methods: We considered a discovery set (n = 17) and a validation set (n = 30) of adult ITP patients, who underwent splenectomy for refractory disease in three Italian referral centers for ITP. Results: We found that the presence of autoimmune comorbidities, daily steroid dose prior to splenectomy, age at diagnosis and age at splenectomy were significantly associated with the outcome. Variables singly associated with an adverse outcome were combined into a clinical and a clinical–pathological score, allowing us to define a “high-risk” group which accounted for about 80% of the disease relapses observed in this cohort. At the same time, a certain clinical–pathological score indicated a “high-risk” group characterized by significantly poorer outcomes. Results were confirmed in the validation cohort. Conclusions: An integrated set of clinical and histological parameters may predict the response to splenectomy in ITP patients. While these findings provide valuable insights, they were derived from a small cohort of patients and therefore require validation in larger, more diverse populations to ensure their generalizability and robustness.