SummaryOral squamous cell carcinoma (OSCC) is a worldwide health problem because it is a great cause of cancer morbidity and mortality. The transforming growth factor‐β1 (TGF‐β1) is involved in the regulation of numerous immunomodulatory processes. Thus, the aim of this case–control study was to investigate the possible association between the TGF‐β1T869C polymorphism and oral cancer. The genomic DNA extracted from peripheral blood of 62 male smoker patients diagnosed with OSCC and 62 smokers without cancer was analysed. The C allele was significantly more prevalent in the oral cancer group than in the controls, and individuals carrying this allele had an estimated 2.73‐fold greater relative risk of developing cancer compared with C allele noncarriers (OR = 2.73, 95% CI = 1.19–6.28). Although T allele was not statistically significant among the controls, considering the genotypic analysis, the TT homozygous genotype showed a protector effect in relation to oral cavity cancer (OR = 0.37, 95% CI = 0.16–0.84). Some clinicopathological features were also analysed for genotype distribution, and no significant differences were observed: tumour size (P > 0.70), nodal status (P > 0.10) and tumour stage (P > 0.70). This is the first report of a study assessing the importance of T869C TGF‐β polymorphism in oral cancer. It is known that the TGF‐β T869C variation results in a Leu10Pro substitution in the signal peptide sequence. Our results suggested that the C allele could increase TGF‐β secretion which suppresses antitumour immune responses and may affect the OSCC risk.