Immune thrombocytopenia (ITP) is an acquired antibody-mediated disease, for which splenectomy remains a curative treatment. We analyzed histology and phenotypes of ITP-splenectomy specimens from 41 adult patients, with different previous ITP-specific treatments, including B-cell-depleting rituximab (RTX) or not, in an attempt to predict splenectomy success or failure on the basis of day 56 postoperative platelet counts. RTX-naive ITP-spleen samples, compared with those from a 20-patient control trauma cohort, contained the following nonspecific, ITP-evocative, white-pulp lesions: follicular helper T-cell (programmed death-1 and inducible T-cell COStimulator) expansion in reactive follicles (P=0.01 and 0.03, respectively) and regulatory T-cell (FOXP3) expansion in the T-cell zone (P=0.049). On comparing ITP-splenectomy samples that would be successful with those that would be failures, only marginal zone hyperplasia differed (P=0.017). Indeed, 13/21 (61.9%) successful splenectomy samples exhibited marginal zone hyperplasia, as opposed to 1/9 (11.1%) failed splenectomy specimens. RTX impact on ITP-splenectomy samples was characterized by white-pulp (P=0.03) and marginal zone atrophies (P=0.01), and periarteriolar T-cell-zone hyperplasia (P<0.0001). The results of this novel comparative study of the histologic patterns of 41 ITP patients' evocative splenic lesions enabled clear description of different ITP morphologies and phenotypes, as a function of prior treatment and splenectomy success or failure.