Diet and inflammation have been suggested to be important risk factors for oral and pharyngeal cancer. We examined the association between dietary inflammatory index (DII™) and oral and pharyngeal cancer in a large case-control study conducted between 1992 and 2009 in Italy. This study included 946 cases with incident, histologically confirmed oral and pharyngeal cancer, and 2,492 controls hospitalized for acute non-neoplastic diseases. The DII was computed based on dietary intake assessed by a valid 78-item food frequency questionnaire and was adjusted for nonalcohol energy intake using the residual approach (E-DII™). Logistic regression models were used to estimate odds ratios (ORs), and 95% confidence intervals (CIs), adjusted for age, sex, non-alcohol energy intake, study center, year of interview, education, body mass index, tobacco smoking, and alcohol drinking. Subjects with higher DII scores (i.e., with a more pro-inflammatory diet) had a higher risk of oral and pharyngeal cancer, the OR being 1.80 (95% CI 1.36–2.38) for the highest versus the lowest DII quartile and 1.17 (95% CI 1.10–1.25) for a one-unit increase (8% of the DII range). When stratified by selected covariates, a stronger association was observed among women (ORquartile4 v.1 3.30, 95% CI 1.95–5.57). We also observed a stronger association for oral cancers and a strong combined effect of higher DII score and tobacco smoking or alcohol consumption on oral and pharyngeal cancer. These results indicate that the pro-inflammatory potential of the diet, as shown by higher DII scores, is associated with higher odds of oral and pharyngeal cancer.