Cytotoxic T-lymphocyte antigen 4 (CTLA-4; CD152) is a secondary receptor of B7 (CD80 and CD86) and shares homology with the CD28 receptor. Although the structures of CTLA-4 and CD28 are very similar, they deliver different costimulatory signals. A functional polymorphism in CTLA-4 exon 1 position +49 that can affect the T-cell response has been reported by several groups. Previous case-control studies also revealed this polymorphism contribute to the risk of autoimmune diseases and common cancers. However, the relationship between CTLA-4 functional polymorphism and nasopharyngeal carcinoma (NPC) susceptibility has not yet been explored. In this study, we performed a case-control study in a Chinese population. Our result showed that the CTLA-4 +49 A>G polymorphism is associated with NPC susceptibility. The subjects carrying the CTLA-4 +49 AA genotype have a approximately 1.8-fold increased risk of NPC (adjust OR 1.83; 95% CI, 1.16-2.93) when compared with the GG genotype.