Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) are CD5+ small B-cell neoplasms (SBCNs) with overlapping features. Flow cytometric immunophenotyping is often used to help differentiate CLL from MCL, and a characteristic CLL phenotype is considered essentially diagnostic. However, previous studies have not specifically examined how well a typical MCL immunophenotype distinguishes MCL from CLL. We identified 28 cases of SBCN with typical flow cytometry-determined MCL immunophenotypes consisting mostly of peripheral blood and bone marrow specimens. Fluorescence in situ hybridization analysis indicated that 57% (16/28) had t(11;14) translocations consistent with MCL, while 32% (9/28) lacked t(11;14) translocations but harbored other cytogenetic abnormalities commonly found in CLL. There were no significant morphologic or immunophenotypic differences between the t(11;14)-positive and t(11;14)-negative cases. Our findings suggest that many blood-based SBCNs with typical MCL immunophenotypes likely represent cases of phenotypically atypical CLL, which would have important clinical implications.