Published data on the association between tumour necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1 or DR4) polymorphisms rs20575 (C626G), rs2230229 (A1322G) and rs20576 (A683C) and cancer risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. A total of nine studies, among which eight articles including 2941 cases and 3358 controls described C626G genotypes, three articles including 736 cases and 668 controls described A1322G genotypes and three studies totalling 1550 cases and 2257 controls described A683C genotypes were involved in this meta-analysis. Overall, all three polymorphisms were associated with cancer susceptibility. For C626G polymorphism, there was no association between C626G polymorphism and the risk of cancer in all genetic models when all the eligible studies were pooled into the meta-analysis. In the subgroup analysis by source of controls, statistically significantly reduced cancer risks were found among groups with population-based controls for CG versus CC (OR=0.77, 95% CI:0.65-0.91, P(heterogeneity)=0.007) and dominant model (OR=0.84, 95% CI:0.72-0.99, P(heterogeneity)=0.409). For A1322G polymorphism, we found it was associated with a significantly elevated cancer risk of all cancer types in different genetic models (homozygote comparison: OR=2.80, 95% CI:1.16-6.76, P(heterogeneity)=0.905; dominant model comparison: OR=1.57, 95% CI:1.02-2.41, P(heterogeneity)=0.167; and recessive model comparison: OR=1.22, 95% CI:0.94-1.60, P(heterogeneity)=0.535). Similar results were obtained from A683C polymorphism (homozygote comparison: OR=3.21, 95% CI:1.26-8.20, P(heterogeneity)=0.012; dominant model comparison: OR=1.61, 95% CI: 1.09-2.36, P(heterogeneity)=0.000; and recessive model comparison: OR=2.79, 95% CI: 1.17-6.68, P(heterogeneity)=0.025). In summary, this meta-analysis suggests that TRAIL-R1 C626G polymorphism is marginally associated with cancer susceptibility, and both TRAIL-R1 A1322G G allele and A683C C allele are associated with increased risk for cancer.