Background: In the head and neck, human papillomavirus-related oropharyngeal squamous cell carcinoma (HPV(+)OPSCC) has a better prognosis and more tumor infiltrating lymphocytes (TILs) compared to its HPV(-) counterpart. Within HPV(+)OPSCC, the prognostic value of TILs in the primary tumor and in metastatic lymph nodes is not well understood. Methods: This is a matched case-control study at a tertiary care center of HPV(+)OPSCC patients who underwent primary surgery between 05/2007–12/2016. Cases developed locoregional recurrence or distant metastases during follow-up, while controls did not during a similar duration of follow-up. Pairs were matched on age, American Joint Committee on Cancer (AJCC) 8^th edition pathologic stage, sex, year of surgery, degree of adjuvant treatment, comorbidities, and smoking status. One representative H&E slide of the primary tumor and lymph node (when nodal disease was present) from each patient was independently reviewed by two pathologists (JG, MR) blinded to outcome, for tumor TILs (tTILs) density (defined as % TILs), presence/absence of desmoplastic stroma, and when stroma was present, for stromal TILs (sTILs) density (defined as relative crowding of TILs). The Brandwein-Gensler pattern of invasion (POI) score was used to grade the primary tumor. Interrater agreement was assessed using Cohen’s kappa. Associations between TILs and time to disease progression were assessed using Cox proportional hazards regression models. Results: 41 case-control pairs (N=82) were included in the study: 38 (46%) were AJCC pStage I, 37 (45%) were pStage II, and 7 (9%) were pStage III; 22 (27%) underwent surgery alone, 15 (18%) underwent surgery with adjuvant radiotherapy, and 45 (55%) underwent surgery with adjuvant chemoradiation. Interrater agreement was fair for tTILs density in the primary tumor (k=0.24) and lymph node (k=0.23), moderate for desmoplastic stroma in the primary tumor (k=0.58) and lymph node (k=0.64), moderate for sTILs density in the primary tumor (k=0.58) and lymph node (k=0.48), and fair for the POI score (k=0.17). tTILs density ≥10% (HR 0.35, 95% CI 0.14-0.90, p=0.028) and a moderate/dense sTILs density (HR 0.15, 95% CI 0.04-0.68, p=0.014) in the primary tumor were significantly associated with decreased risk of disease progression. An aggressive POI score of III or IV was significantly associated with increased risk of disease progression (HR 4.00, 95% CI 1.34-11.96, p=0.013). None of the study measures in the lymph node were significantly associated with disease progression. Conclusions: In HPV(+)OPSCC, a higher density of tumor and stromal TILs and nonaggressive POI in the primary tumor specimen may indicate a lower risk of disease progression. TILs may serve as a powerful prognostic marker for the adaptive immune response to this disease.