The promoter variants of TNF-α, a major regulator of immune and inflammation responses, have been implicated in cancer development and prognosis. Thus, we investigated associations between four TNF-α promoter variants and risk of recurrence of squamous cell carcinoma of the oropharynx (SCCOP). We evaluated associations of four TNF-α polymorphisms with risk of recurrence in a cohort of 846 patients with SCCOP. Log-rank test and multivariable Cox models were used to evaluate associations. Compared with patients with variant genotypes of the TNF-α -308 and TNF-α -863 polymorphisms, patients with common homozygous genotypes had worse disease-free survival (log-rank p = 0.0002 and p < 0.0001, respectively) and increased risk of SCCOP recurrence (HR, 1.9, 95% CI, 1.3-2.8 and HR, 1.9, 95% CI, 1.3-2.7, respectively) after multivariable adjustment. Furthermore, among patients with HPV16-positive tumors, those with common homozygous genotypes of the TNF-α -308 and -863 polymorphisms had worse disease-free survival (log-rank p = 0.005 and p = 0.007, respectively) and higher recurrence risk than patients with variant genotypes of these polymorphisms (HR, 5.1, 95% CI, 1.4-18.4 and HR, 3.7, 95% CI, 1.5-9.1, respectively), while no such significant associations were found for TNF-α -857 or -1031 polymorphisms. Our findings suggest that TNF-α -308 and -863 polymorphisms may modulate the risk of SCCOP recurrence in patients with HPV16-positive tumors. However, larger studies are needed to validate these results.