Background: Chemoradiation is the standard of care for human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). However, not all patients would 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 in stage I and stage II HPV-associated OPSCC. Methods: Radiographic scans for 491 patients with stage I and stage II HPV-associated OPSCC were acquired from 4 independent sources and divided into three cohorts D₁-D₃. D₁ comprised computed tomography (CT) scans from 60 radiotherapy treated patients and was used to identify prognostic features via a LASSO Cox model to predict overall and disease-free survival. The prognostic performance of pRiS was evaluated on two test sets (D₂, n = 162; D₃, n = 269) using concordance index (C-index). An integrated nomogram was developed to demonstrate the incremental value of the pRiS to the existing clinical factors for individualized survival estimation. Patients from D₂ and D₃ who received either radiotherapy alone or chemoradiation were used to validate pRiS as predictive of added benefit of chemotherapy. Results: Seven radiomic features were selected to construct the image biomarker 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 both 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. Conclusions: The proposed radiomic signature was prognostic of patient survival and the binary pRiS group informed chemotherapy benefit for stage I and II HPV-associated OPSCC patients.