Background: SCCAC is a human papilloma virus (HPV) associated cancer that is potentially curable with CMT, commonly associated with HIV infection, and characterized by high local regional failure (LRF) rates. Since cetuximab enhances the effect of radiation in HPV-associated oropharyngeal SCC, we evaluated the efficacy and toxicity of cetuximab plus CMT in SCCAC. Methods: We performed 2 concurrently planned and conducted phase II trials of cetuximab plus CMT in stage I-III SCCAC without (E3205) and with (AMC045) HIV infection. CMT included cisplatin (75 mg/m2) and 5-FU (1000 mg/m2/day x 4 days) x 2 cycles plus RT (45-54 Gy), plus 2 cycles of neoadjuvant cisplatin/5-FU in the first 28 patients in E3205 prior to a study amendment. Cetuximab (400 mg/m2 IV, then 250 mg/m2 IV weekly x 8 weeks) began 1 week prior to CMT. The studies were designed to detect at least a 50% reduction in 3-year LRF rate (35% to 17.5%, 1-sided alpha 0.10, power 90%). Secondary objectives included progression free survival (PFS) and overall survival (OS). Results: The characteristics of the study population and efficacy results are summarized below, indicating higher rates of node positive disease in AMC 045 (47%) and E3205 (54%) compared with R9811 (26%) and ACTII (32%). The majority of patients completed protocol therapy in AMC045 (82%) and E3205 (79%), rates of grade 4 toxicity were similar (32% in E3205, 26% AMC45), and 4% had treatment-associated deaths. Conclusions: Patients with SCCAC with and without HIV infection exhibited similar rates of completing therapy (80%) and clinical outcomes with cetuximab plus CMT. LRF rates were lower compared with historical data using similar definitions. The findings suggest that patients with stage I-III HIV-associated SCCAC should be treated with curative intent similar to immunocompetent patients, and that addition of cetuximab to CMT may reduce LRF. Clinical trial information: 00324415, 00316888.