Hypoxia-inducible factor-1 (HIF-1) influences cancer progression and metastasis through various mechanisms, and HIF-1α polymorphisms are reportedly associated with many cancers; however, the associations of HIF-1α P582S and A588T polymorphisms with the risk of digestive system cancer remain inconclusive. To understand the role of HIF-1α P582S and A588T genotypes in digestive cancer development, we conducted a comprehensive meta-analysis involving 1,517 cases and 3,740 controls. Overall, the P582S polymorphism was not significantly associated with digestive system cancers in all genotypes. By contrast, the A588T polymorphism was significantly associated with digestive system cancers in the dominant model (TT/AT vs. AA: OR = 3.17, 95% CI: 1.21, 8.25; P heterogeneity < 0.001). In subgroup analysis for cancer types, the two polymorphisms were only associated with increased risk of pancreatic cancer (P582S: SS vs. PP: OR = 2.51, 95% CI: 1.31, 4.81; SS vs.
Pp/ps: OR = 8.73, 95% CI: 1.33, 57.1; A588T: TT vs. AA: OR = 9.30, 95% CI: 1.12, 77.6; P heterogeneity = 0.478; TT vs.
Aa/at: OR = 3.14, 95% CI: 1.99, 4.97; P heterogeneity = 0.098; TT/AT vs. AA: OR = 8.65, 95% CI: 1.05, 71.6; P heterogeneity = 0.418). According to the source of ethnicity, the P582S and the A588T polymorphisms are both significantly associated with an increased risk of cancer among Caucasians in the homozygote model (SS vs. PP: OR = 2.41, 95% CI: 1.24, 4.691; P heterogeneity = 0.010; TT vs. AA: OR = 98.6, 95% CI: 4.37, 2,224; P heterogeneity = 0.040) and the recessive model (SS vs.
Pp/ps: OR = 9.48, 95% CI: 1.12, 80.3; P heterogeneity < 0.001; TT vs.
Aa/at: OR = 82.7, 95% CI: 3.79, 1,802; P heterogeneity = 0.041). Our findings suggest that the HIF-1α A588T polymorphism is significantly associated with higher cancer risk and the P582S polymorphism is significantly associated with pancreatic cancer risk. Furthermore, the effect of both polymorphisms on digestive system cancer is more pronounced among Caucasians than that among Asians.