Chemoradiation is a common therapeutic regimen for human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). However, not all patients benefit from chemotherapy, especially patients with low-risk characteristics. We aim to develop and validate a prognostic and predictive radiomic image signature (pRiS) to inform survival and chemotherapy benefit using computed tomography (CT) scans from 491 stage I and II HPV-associated OPSCC, which were divided into three cohorts D1–D3. The prognostic performance of pRiS was evaluated on two test sets (D2,n= 162; D3,n= 269) using concordance index. Patients from D2and D3who received either radiotherapy alone or chemoradiation were used to validate pRiS as predictive of added benefit of chemotherapy. Seven features were selected to construct pRiS, which was found to be prognostic of overall survival (OS) on univariate analysis in D2(hazard ratio [HR] = 2.14, 95% confidence interval [CI], 1.1–4.16,p= 0.02) and D3(HR = 2.74, 95% CI, 1.34–5.62,p= 0.006). Chemotherapy was associated with improved OS for high-pRiS patients in D2(radiation vs chemoradiation, HR = 4.47, 95% CI, 1.73–11.6,p= 0.002) and D3(radiation vs chemoradiation, HR = 2.99, 95% CI, 1.04–8.63,p= 0.04). In contrast, chemotherapy did not improve OS for low-pRiS patients, which indicates these patients did not derive additional benefit from chemotherapy and could be considered for treatment de-escalation. The proposed radiomic signature was prognostic of patient survival and informed benefit from chemotherapy for stage I and II HPV-associated OPSCC patients.