Extranodal nasal-type natural killer cell lymphoma (ENKL) is a high-grade malignancy and is associated with Epstein-Barr virus (EBV) latent infection. Little is known about its molecular abnormalities. Here, we studied the expression of Skp2 and p27 proteins in 48 cases of ENKL, and we evaluated their correlations with EBV status and clinical outcomes. EBV infection was observed in 90% of the cases. In all, 71% of the ENKLs were positive to Skp2 and 73% were negative to p27. A significant negative correlation was observed between the expression of Skp2 and p27 proteins (P = 0.022). Fifty-eight percent of the cases were Skp2+/p27- phenotype and correlated with EBV status (P = 0.047). The overall survival was influenced by the expression of Skp2, p27, and Skp2/p27. Patients with Skp2+, p27-, and Skp2+/p27- phenotypes had worse overall survival (P < 0.01, P = 0.016, and P < 0.01, respectively). Multivariance analysis showed the Skp2/p27 expression profile was an independent prognostic factor for overall survival (RR = 3.09, P < 0.01, 95% CI: 1.27-7.51). In conclusion, the Skp2/p27 expression profile is a helpful prognostic factor for ENKL. Latent EBV infection may increase the expression levels of Skp2, and consequently, p27 protein degradation is accelerated. EBV may be a good target for treatment of EBV-associated ENKL.