Interleukin (IL)-22 has been implicated in inflammation and tumorigenesis. To date, no studies have investigated the role of IL-22 polymorphism in the carcinogenesis of gastric cancer (GC). In this study, we aimed to investigate the association of IL-22 polymorphisms with the risk of GC in a Chinese population. One hundred eight GC patients and 110 healthy controls were included in the study. IL-22 rs1179251, rs2227485, and rs2227473 polymorphisms were determined by PCR amplification and DNA sequencing. Haplotypes were constructed, and a possible association of these haplotypes with GC was assessed. The distribution of IL-22 rs1179251 polymorphism with clinical parameters was also analyzed. The IL-22 rs1179251 polymorphism was significantly associated with an increased risk of GC (p  0.05). Three possible haplotypes (C(rs1179251)-C(rs2227485)-G(rs2227485), C(rs1179251)-T(rs2227485)-G(rs2227485), and G(rs1179251)-T(rs2227485)-A(rs2227485)) were identified, but no associations were found between these and the risk of GC (p > 0.05). In summary, our study demonstrates that the rs1179251 polymorphism of IL-22 was associated with an increased risk of GC and may influence the progression of GC. Future larger studies with other ethnic populations are required to confirm these findings.