Tumor necrosis factor-alpha (TNF-α) has been proposed to contribute to the development of upper aerodigestive tract (UADT) cancer that is characterized by poor prognosis. The G-to-A nucleotide change at -308 of the TNF-α gene (-308G/A polymorphism) can increase the expression level of TNF-α and thus may affect the genetic susceptibility of UADT cancer. The association between the -308G/A polymorphism and UADT cancer has been widely studied, but the results published are quite controversial. To obtain a more precise conclusion, we performed a meta-analysis including 1,751 patients and 3,345 controls. The results indicated that the AA genotype of the -308G/A polymorphism had a 54%-increased risk of UADT cancer, compared with the G carriers (GG and GA genotypes) [odds ratio (OR) = 1.54, 95% confidence interval (CI): 1.07-2.21]. After stratified by ethnicity, the AA genotype was associated with increased risk of UADT cancers in South Asians (OR = 33.18 and 95% CI: 1.92-573.62 for AA vs. GA+GG) but not in Caucasians or East Asians. After stratified by tumor site, the -308G/A polymorphism was associated with increased risks of oropharynx cancer (OR = 2.68 and 95% CI: 1.34-5.35 for AA vs. GA+GG) but not associated with esophagus or larynx cancer. After stratified by histological type, the -308G/A polymorphism was associated with increased risks of squamous cell carcinoma (OR = 1.81 and 95% CI: 1.15-2.84 for AA vs. GA+GG) but not associated with adenocarcinoma. Our results indicate that the -308G/A polymorphism might contribute to an increased risk of UADT cancer susceptibility.