Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults, accounting for nearly 40% of all non-Hodgkin's lymphomas. As cell proliferation is essential for tumor growth, analysis of the cell cycle might give additional information on tumor progression. Although markers distinctive for cell-cycle regulation in DLBCL have been addressed, less attention has been paid to cyclin H in DLBCL with respect to its prognostic and potential therapeutic implications. Cyclin H occurs as a component of the cyclin H/Cdk 7/Mat 1 complex. Cyclin H is also a substrate of protein kinase 2, a ubiquitously expressed serine/threonine protein kinase required for cell viability and cell-cycle progression. We evaluated the expression of cyclin H by immunohistochemistry in 301 DLBCLs in a tissue microarray format. Validation was done by performing quantitative real-time polymerase chain reaction and Western blotting experiments for cyclin H. We studied the relationship between cyclin H expression in comparison to other cyclins (A, B1, D1, D3, and E) and the proliferation marker Ki-67. Reduced or absent cyclin H expression was seen in 14.5% of the DLBCL cases. Interestingly, reduced or absent cyclin H expression was correlated with lower expression of proliferation marker Ki-67 (P < .0001), cyclin B1 (P = .0001), cyclin D3 (P = .0007), and cyclin E (P < .0001). Reduced or absent cyclin H expression was significantly associated with poor overall survival, in both the univariate (P = .0286) and multivariate analysis with International Prognostic Index (P = .0180). Our study demonstrates the independent prognostic value of cyclin H expression in DLBCL and proposes its use as a prognostic marker.