Diets high in fruits and vegetables and low in red meat intake have been associated with decreased risk of head and neck cancer. Additionally, chronic inflammation pathways and their association with cancer have been widely described. We hypothesized a pro-inflammatory diet, as measured by the Dietary Inflammatory Index (DII®), is associated with increased risk of head and neck cancer. We used the Carolina Head and Neck Cancer (CHANCE) study, a population-based case-control study of head and neck squamous cell carcinoma. Cases were recruited from a 46-county region in central North Carolina. Controls, frequency-matched on age, race, and sex, were identified through the North Carolina Department of Motor Vehicle records. The DII score, adjusted for energy using the density approach (E-DII), was calculated from a food frequency questionnaire and split into four quartiles based on the distribution among controls. Adjusted odds ratios (ORs) were estimated with unconditional logistic regression. Cases had higher E-DII scores (i.e., a more pro-inflammatory diet) compared with controls (Mean: -0.14 versus -1.50; p-value <0.001). When compared with the lowest quartile, the OR for the highest quartile was 2.91 (95% confidence interval (CI): 2.16-3.95), followed by 1.93 (95% CI: 1.43-2.62) for the 3^rd quartile, and 1.37 (95% CI: 1.00-1.89) for the 2^nd quartile. Both alcohol and smoking had a significant additive interaction with E-DII (smoking relative excess risk due to interaction (RERI): 2.83; 95% CI: 1.36-4.30 and alcohol RERI: 1.75; 95% CI: 0.77-2.75). These results provide additional evidence for the association between pro-inflammatory diet and head and neck cancer. This article is protected by copyright. All rights reserved.