The comparative efficacy of cisplatin (CDDP) versus cetuximab (CTX) delivered concurrently with radiation for locally advanced, non-metastatic, oropharyngeal squamous cell carcinoma (OPSCC) continues to be evaluated. The linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database was used to identify and compare patient and disease profiles, mortality, toxicity, and overall cost in oropharynx cancer patients undergoing definitive concurrent chemoradiation (CRT) with CDDP or CTX between 2006 and 2011. Unadjusted and adjusted analyses and logistic regression were performed. The primary outcome was 2-year overall survival (OS). The analytic sample comprised 348 patients. The sample was nearly evenly split between those who received CDDP and CTX. Older age (OR, 0.15; 95% CI 0.08-0.30; P < .001), African American race (OR, 0.22; 95% CI 0.05-0.84; P = .027), and those with a Charlson Comorbidity Index ≥2 (OR, 0.26; 95% CI 0.12-0.59; P = .001) were less likely to receive concurrent CDDP. Two-year OS was inferior with CTX in the Cox proportional hazards model (HR, 1.91; 95% CI 1.20-3.05; P = .006). Antiemetic use was statistically significantly higher with CDDP (92% vs 44%; P < .001). In the multivariate model, mean per patient spending for CTX was significantly higher than CDDP ($61,621 versus $47,216, P = .002). Older age, African American race, and worse co-morbidity status predicted the use of CTX. CDDP is associated with improved OS, slightly lower overall cost, and higher antiemetic usage. Concurrent CDDP may be the favored chemotherapy agent, with CTX based therapy reserved for those who otherwise cannot tolerate concurrent CDDP in locally advanced OPSCC.