CONTEXT.­: Immunophenotypic variations in mantle cell lymphoma (MCL) from the classic CD5+/CD10-/CD23-/FMC-7+ immunophenotype have been reported in the literature, but correlation with clinical behavior and outcome has not been fully studied. OBJECTIVE.­: To investigate clinicopathologic and prognostic differences between immunophenotypically aberrant MCL and immunophenotypically typical MCL. DESIGN.­: We evaluated differences in clinical presentation, laboratory parameters, prognostic indices, response to initial treatment, and progression-free and overall survival between patients with aberrant MCL and patients with immunophenotypically typical MCL. RESULTS.­: There were 158 patients with newly diagnosed cyclin D1 or t(11;14)(q13;q32)+ MCL identified in the original search, of which, 29 patients (18%) showed immunophenotypic aberrancies, with CD23 coexpression being the most common. When compared with 33 randomly selected patients with immunophenotypically typical MCL, statistically significant differences were seen in white blood cell counts ( P = .02), in the presence of absolute lymphocytosis ( P = .03), in the MCL International Prognostic Index score ( P = .02), and in response to initial treatment ( P = .04). The "immunophenotypic status" of the MCL was the only independent factor associated with response to treatment ( P = .05), but not with the MCL International Prognostic Index score, absolute lymphocytosis, or white blood cell count. No significant differences were seen for progression-free or overall survival. CONCLUSIONS.­: Immunophenotypic variations in MCL are associated with differences in clinical presentation and response to therapy when compared with immunophenotypically typical MCL. However, with current intensive frontline immunochemotherapy, immunophenotypic aberrations do not appear to affect progression-free or overall survival.