Purpose: TGF beta 1 plays a critical role in inflammation and immune responses and treatment response and survival. TGF beta 1 variants may affect its expression level or functional efficiency, thus modifying tumor status and survival in human papillomavirus (HPV)-positive squamous cell carcinoma of the oropharynx (SCCOP). Experimental Design: We determined tumor HPV16 status and genotyped three TGF beta 1 polymorphisms in 564 incident SCCOP patients treated with radiotherapy or chemoradiation. Univariate and multivariable Cox models were used to evaluate the associations between the three polymorphisms and survival. Results: Overall, 85% of patients (482 of 564) had HPV16-positive SCCOP. We found that TGFb1 rs1982073 had statistically significant associations with survival, whereas TGF beta 1 rs1800469 and TGF beta 1 rs1800471 did not. Patients with TGF beta 1 rs1982073 CT/CC variant genotypes had significantly better over-all, disease-specific, and disease-free survival compared with those with the corresponding common homozygous TT genotype (all log-rank: P < 0.001). Furthermore, these genotypes were significantly associated with an approximately 5 times reduced risk of overall death, death owing to disease, and recurrence after multivariable adjustment. Moreover, the stratified analyses by tumor HPV status indicated that the significant effects of TGF beta 1 rs1982073 polymorphism on survival were found among HPV16-positive SCCOP patients only. Finally, the functional relevance of these variants was further characterized. Conclusions: Our findings support that the TGF beta 1 rs1982073 polymorphism plays a significant role in the prognosis of SCCOP, especially in HPV16-positive SCCOP patients treated with chemoradiation. Prospective studies with larger sample sizes are needed to confirm these findings. Clin Cancer (C) 2018 AACR.