The role of angiopoietin-like 3 (ANGPTL3) in blood lipid levels, cardiovascular disease risk, and glucose metabolism has received wide attention. This study aimed to examine whether rs11207997 in ANGPTL3 is associated with a 10-year risk of diabetes mellitus (DM) and if the association is modified by the consumption of certain food groups or nutrients. A prospective cohort study was designed using the Ansan-Ansung data of the Korean Genome and Epidemiology Study (n = 7,358; age ≥40 years at baseline). Participants with the T allele of rs11207997, particularly TT homozygotes, had lower triglyceride (TG) and total cholesterol levels than those with CC. There was no association with fasting blood glucose or other biochemical parameters. ANGPTL3 mRNA was positively associated with circulating TG levels and blood pressure (all p < 0.05). Cox proportional hazard models showed that the rs11207997 T allele is associated with a lower risk of DM after adjusting for covariates (hazard ratio: 0.90, 95% confidence interval: 0.812-0.998, p = 0.046). Furthermore, the association between rs11207997 and the risk of DM was modified by dietary factors. These associations were no longer statistically significant when additionally adjusted for baseline TG, a potential mediator. Our data suggest that genetic variation of rs11207997 in the ANGPTL3 gene is associated with risk of DM, possibly through contributing to a lifelong set point of TG.