Mantle cell lymphoma (MCL) represents 4% to 9% of all non-Hodgkin lymphomas and is characterized by CD5 and cyclin D1 expression and t(11;14)(q13;q32). However, about 5% of MCL lack CD5 expression and is poorly characterized. Here, we present 58 patients with CD5 negative (CD5) MCL and compared them with a group of 212 typical CD5 positive (CD5) MCL cases. There were 39 men and 19 women with a median age of 66 years (range, 36 to 88). Compared with CD5 positive (CD5) MCL patients, patients with CD5 MCL showed a lower male-to-female ratio (P=0.006) and a higher frequency of "bone marrow non-nodal" presentation (P=0.01). All other clinicopathologic features, including the frequency of SOX11 expression, were similar between the 2 groups. Treated with similar regimens, patients with CD5 MCL showed a significantly longer progression-free survival (PFS) (P=0.01) and a tendency for longer overall survival (OS; P=0.078) than CD5 positive (CD5) MCL patients. Univariate analysis showed of the well-known poor prognostic factors, only Mantle Cell Lymphoma International Prognostic Index was an inferior prognostic factor and blastoid/pleomorphic morphology and high Ki67 were not associated with prognosis in CD5 MCL patients. Multivariate Cox regression analysis showed CD5 expression was an independent prognostic factor for PFS (P=0.031) but not OS in MCL patients. In conclusion, the results suggest that patients with CD5 MCL have a more favorable prognosis than CD5 MCL patients, although the clinicopathologic features of both groups are largely similar. CD5 MCL may represent a distinct variant of MCL and needs to be included in the differential diagnosis of CD5 small B-cell lymphomas.