BACKGROUND: Immunophenotyping has a central role in CLL. However, CLL is a very heterogenous disease, both morphologically and immunophenotypically; thus, its diagnosis may prove a challenge. We investigated CD81 ex-pression in the differential diagnosis of CLL and MCL. METHODS: We retrospectively examined CD81 expression with 8 color Multiparameter Flow cytometry devices in 101 CLL and 19 MCL cases. RESULTS: We found negative CD81 expression in CLL cases whereas it was positive in MCL cases. CONCLUSIONS: Our results suggest that CD81 may be a valuable marker for the differential diagnosis of CLL. We are of the opinion that it should be definitely included in the diagnostic algorithm for CLL.