Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma worldwide. Both morphologically and prognostically, it represents a disease of a diverse spectrum. S-phase kinase-associated protein 2 (Skp2) is a member of mammalian F-box proteins, which displays S-phase-promoting function through ubiquitin-mediated proteolysis of the cyclin-dependent kinase inhibitor, p27. The aim of this study is to evaluate the prognostic value of Skp2 in DLBCL (70 cases) by immunohistochemical staining technique, and its correlation with the clinicopathological features and survival. Five (25%) control cases (reactive follicular hyperplasia) showed high Skp2 expression compared with 52.9% of DLBCL using 10% as a cutoff point with a significant difference (P=0.04). Skp2 was seen staining the large cells in proliferating germinal centers of the control group. High Skp2 expression in DLBCL was associated with several progressive parameters, such as advanced stage (P=0.036), involvement of more than one extranodal site (P=0.05), and high proliferation (P=0.0001). It was also significantly associated with the presence (P=0.007) and extent (P=0.002) of necrosis and inversely correlated with p27 expression (P=0.0001). From this study, Skp2 expression in DLBCL identified subset of cases characterized by aggressive features such as advanced stage, increased number of extranodal sites, high proliferation, and shorter survival time. The association of Skp2 with necrosis may be a reflection of its ability in promoting proliferative tumor capacity.