Background <p>Evidence for a potential link between dietary inflammatory potential and inflammatory bowel disease is limited, and the moderating role of genetic susceptibility remains to be assessed.</p> Objective <p>To evaluate energy-adjusted dietary inflammatory index (E-DII) for the associations with incident Crohn’s disease (CD) and ulcerative colitis (UC) and the role of genetic susceptibility.</p> Methods <p>A total of 205,706 UK Biobank participants who were aged 39–72 years and had no known CD or UC at baseline (2006–2010) were included. The E-DII score was calculated based on energy-adjusted average intakes of 33 food or nutrient items derived from up to five 24-hour dietary recalls. Multivariable Cox regression models were used estimate hazard ratios (HRs) with 95% confidence interval (CI) for incident CD and UC.</p> Results <p>During a median 12.3 years of follow-up, 382 incident CD and 798 incident UC cases were ascertained. A higher E-DII score was not associated with risk of CD (HR _{Q4 VS. Q1} = 1.28, 95% CI: 0.94–1.74; <i>P</i>-trend = 0.09) or UC (HR _{Q4 VS. Q1} = 1.10, 95% CI: 0.90–1.36; <i>P</i>-trend = 0.17). There was an interaction between the E-DII and the polygenic risk score (PRS) for CD on incident CD (<i>P</i>-interaction = 0.023), with an association only among participants with a high PRS (HR _{Q4 VS. Q1} = 1.64, 95% CI: 1.03–2.61) (<i>P</i>-interaction = 0.023). As compared with the participants with a low PRS for CD and a low E-DII score, participants with high levels of both scores had a particularly higher risk of CD (HR = 3.12; 95% CI: 1.74–5.60).</p> Conclusions <p>The association of dietary inflammatory potential with incident CD appears to be amplified by high genetic susceptibility to CD.</p>