Epidemiological studies have assessed the association between HIF-1α polymorphisms and cancer risk. However, the results remained conflicting rather than conclusive. Therefore, we performed a systematic review to provide a complete picture and conducted a meta-analysis to derive a precise estimation. We searched PubMed, Embase, and China National Knowledge Infrastructure (CNKI) databases until July 2013 to identify eligible studies. Data sets (43) from 39 studies with a total of 10,841 cases and 14,682 controls were included. The most commonly investigated polymorphism was C1772T, followed by G1790A, C111A, and rs2057482. Overall, C1772T and G1790A but not rs2057482 were associated with increased risk for cancer. When stratified by cancer type, C1772T was associated with increased risk for cervical cancer (T/T vs. C/T+C/C: OR = 8.80, 95 % CI = 2.30-33.70), prostate cancer (T vs. C: OR = 1.54, 95 % CI = 1.04-2.30), and other cancers (T vs. C: OR = 1.42, 95 % CI = 1.07-1.89), but not oral, breast, colorectal, endometrial, lung, and bladder cancers or renal cell carcinoma. G1790A was associated with marginal but insignificant risk for prostate cancer (A vs. G: OR = 1.46, 95 % CI = 1.00-2.13, P = 0.056) and with increased risk for oral (A vs. G: OR = 9.66, 95 % CI = 1.31-71.15), lung (A vs. G: OR = 2.27, 95 % CI = 1.74-2.96), and other cancers (A vs. G: OR = 2.06, 95 % CI = 1.26-3.37) and renal cell carcinoma (A/A vs. G/A+G/G: OR = 3.05, 95 % CI = 1.36-6.84), but not breast, colorectal, cervical, or bladder cancer. Furthermore, we detected increased cancer risk in haplotypes TA and CA and in those carrying at least one risk allele, and decreased cancer risk in haplotype TG regarding C1772T and G1790A polymorphisms. Further well-designed studies on various cancer types are warranted to verify our findings.