Background Various dietary components have been studied in relation to overall mortality; however, little is known about the relationship between the inflammatory potential of overall diet and mortality. Materials and methods We examined the association between the dietary inflammatory index (DII) and mortality in the National Health and Nutrition Examination Survey III follow-up study. The DII was computed from baseline dietary intake assessed using 24-h dietary recalls (1988–1994). Mortality was determined from the National Death Index records through 2006. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95 % confidence interval (95 % CI). During the follow-up, 2795 deaths were identified, including 1233 due to cardiovascular disease (CVD), and 615 due to cancer, 158 of which were due to digestive-tract cancers. Results Multivariate Cox proportional hazards regression analyses, adjusting for age, race, diabetes status, hypertension, physical activity, body mass index, poverty index, and smoking, revealed positive associations between higher DII scores and mortality. Comparing subjects in DII tertile 3 versus tertile 1, significant associations were noted for all-cause mortality (HR Tertile3vs1 1.34; 95 % CI 1.19–1.51, P trend  < 0.0001), CVD mortality (HR Tertile3vs1 1.46; 95 % CI 1.18–1.81, P trend  = 0.0006), cancer mortality (HR Tertile3vs1 1.46; 95 % CI 1.10–1.96, P trend  = 0.01), and digestive-tract cancer mortality (HR Tertile3vs1 2.10; 95 % CI 1.15–3.84, P trend  = 0.03). Conclusion These results indicate that a pro-inflammatory diet, as indicated by higher DII scores, was associated with higher risk of all-cause, CVD, and cancer mortality.