Interleukin-23 receptor (IL-23R) is a key element in the T-helper 17 cell-mediated inflammatory process, which plays an important role in the pathogenesis of cancer. In this study, we examined whether genetic polymorphisms in IL-23R are associated with cancer risk in 4936 cancer patients and 5664 control subjects from eastern and southern Chinese populations. We found that the C allele of the rs10889677A>C polymorphism in the 3'-untranslated region of IL-23R was inversely associated with risk of multiple types of cancer, including breast cancer, lung cancer and nasopharyngeal carcinoma. Healthy controls who harbored the rs10889677C allele had significantly decreased cancer risk (odds ratio = 0.74, 95% confidence interval = 0.71-0.78) compared with those who harbored the rs10889677A allele. Biochemical analysis demonstrated that the rs10889677A allele disrupted the binding site for the microRNA miR-let-7f, thereby increasing the transcription of the IL-23R in vitro and in vivo. Furthermore, cancer-free individuals carrying the rs10889677CC homozygous genotype had a lower proportion of regulatory T cells (Tregs) and a higher T-cell proliferation rate upon stimulation with concanavalin A than individuals carrying the rs10889677AA homozygous genotype. Our findings indicate that the IL-23R rs10889677A>C polymorphism may influence T-cell proliferation, resulting in changes in the levels of Tregs in vivo and modifying cancer susceptibility.