Vasoactive intrinsic peptide receptor (VIPR2), a circadian gene, is involved in metabolic homeostasis and metabolic syndrome (MetS). Seaweeds contain polysaccharides that regulate metabolic homeostasis, possibly by altering the effects of VIPR2 variants. We examined the relationship between VIPR2 expression and the incidence of MetS based on seaweed consumption. This study included 4979 Koreans aged ≥40 years using data from the Ansan-Ansung cohort of the Korean Genome and Epidemiology Study. The total seaweeds included were laver, kelp, and sea mustard. A multivariable Cox proportional hazards model was used to analyze the interactions between the VIPR2 rs6950857 genotype associated with MetS incidence and seaweed intake after adjusting for covariates such as region. A total of 2134 patients with MetS were followed for an average of 8.9 years. In men with the GG genotype of rs6950857, the highest quintile of seaweed consumption was associated with a decreased incidence of MetS compared with that of the lowest quintile (hazard ratio, 0.78; 95% confidence interval, 0.62-0.98). We identified a unique association between the rs6950857 genotype, seaweed intake, and MetS. These findings highlight the importance of VIPR2 and the regulatory role of seaweed consumption in MetS incidence.