Interleukin-18 (IL-18) is a pleiotropic, pro-inflammatory cytokine with dual effects on tumor development and progression. The -607(C/A) and -137(G/C) polymorphisms in IL-18 gene region have been implicated in cancer risk; however, data from published studies with individually low statistical power are conflicting. To clarify the role of IL-18 -607(C/A) and -137(G/C) genotype in global cancer, we examined all the available published studies through a pooled analysis approach. Overall, IL-18 -607A allele was associated with increased total cancer risk when compared with -607C allele (OR=1.14, 95% CI=1.01-1.28, P=0.010), as well as in the heterozygote comparison (OR=1.10, 95% CI=1.04-1.15, P=0.256) and the dominant model (OR=1.07, 95% CI=1.03-1.11, P=0.124). Furthermore, IL-18 -137(G/C) polymorphism was associated with increased nasopharyngeal carcinoma risk. In the stratified analysis for -607(C/A) polymorphism, a significantly increased cancer risk in Asian population was found, as well as subgroup in source of control. Similar results were found in the stratified analysis for -137(G/C) polymorphism. Our pooled analysis supported that IL-18 is a good candidate for large-scale epidemiological case-control studies that may be a low-penetrance susceptibility biomarker for cancer.