Objective: To evaluate the impact of p16INK4a (p16) expression on clinical efficacy of induction low-dose fractionated radiation therapy (LDFRT) with concurrent chemotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). Study Design: Historical cohort study. Setting: Tertiary medical center. Methods: A total of 66 Patients with locally advanced SCCHN were enrolled in 2 clinical trials using paclitaxel, carboplatin, and concurrent LDFRT induction therapy. Patients were evaluated for response to induction by a multidisciplinary team and then were given definitive treatment. Adequate tissue samples from the pretreatment biopsies of 42 individuals were identified and analyzed for p16 expression. Expression was correlated with clinical outcomes. Results: Of 42 tumors, 15 (35.7%) were positive for p16. Patients with p16-positive tumors had improved response to induction, but this was not statistically significant ( P = .06). Five-year overall survival was 80% in p16-positive patients and 58% in p16-negative patients ( P = .025). Conclusions: p16 Expression affects treatment response in patients treated with induction LDFRT with concurrent chemotherapy. This is similar to results reported for standard induction chemotherapy.