Background. Dietary patterns play important role in Helicobacter pylori (H. pylori) infection. We aimed to investigate the potential relationship between Dietary Inflammation Index (DII) and H. pylori infection in US adults. Methods. This cross-sectional study was based on National Health and Nutrition Examination Survey (1999–2000). Individuals aged ≥20 years who provided a 24 hr dietary intake history and underwent H. pylori testing were included in the analysis. Multivariate weighted logistic regression analysis, smooth curve fitting, and subgroup analysis were used to investigate the relationship between DII and H. pylori infection. Subgroup analyses were based on demographic and clinical variables. Results. There were 4,000 individuals enrolled in our final analysis. The overall mean age was 45.92 years and 46.77% were males. The overall prevalence of H. pylori infection in the study population was 45.9%. The smooth curve fitting analysis indicated a near-linear relationship between DII and H. pylori. In multivariate weighted logistic regression analysis, the odds ratio (OR) of DII is 1.17 (95% confidence interval (CI), 1.09–1.27) for H. pylori infection. In subgroup analysis, DII still increased the risk of H. pylori infection independently. Conclusions. The increased DII levels were associated with an increased risk of H. pylori infection among US adults. Further studies are needed to elucidate the exact mechanisms of DII and H. pylori infection.