Histologic and phenotypic analyses of splenectomy samples from 17 patients with common variable immunodeficiency (CVID) showed the following nonspecific, evocative, white-pulp lesions: white-pulp hyperplasia (WPH) with reactive follicles, giant follicles (GFs), marginal zone hyperplasia, periarteriolar T-zone hyperplasia (PATH) and/or granulomas, which enabled us to discern 2 groups: the first (n=6) composed of WPH with reactive follicles without granulomas, and the second (n=9) characterized by the presence of granulomas with or without WPH. All specimens were Epstein-Barr virus negative by in situ hybridization. Molecular analyses revealed a polyclonal immunoglobulin heavy chain gene (IGH) rearrangement (n=12). WPH-only patients were mostly female individuals and younger at CVID onset, diagnosis, and splenectomy, but their interval between the first symptom and diagnosis was longer; they had more associated infectious events, autoimmune disease, pulmonary complications, and liver regenerative nodular hyperplasia; their IgG, IgA, and IgM concentrations were also higher. Granuloma-group patients were mostly male individuals; were older at CVID onset, diagnosis, and splenectomy; had disseminated granulomatous disease, but infectious events, autoimmune disease, pulmonary complications, and liver regenerative nodular hyperplasia were less common; their immunoglobulin concentrations were lower. Histologic comparisons between the WPH-only and granuloma groups showed more intense WPH and more intense marginal zone hyperplasia and fewer GFs in the former versus more developed PATH and more common GFs in the latter. The results of this novel comparative study of the histologic patterns of 17 CVID patients' evocative splenic lesions suggested different biological and clinical profiles.