Fatty acids (FAs) involvement in atopic dermatitis (AD) prevention is inconclusive, and the modification effect by genetic risk profiles remains unknown. The aim of this study is to explore the association between circulating FAs, genetic risk factors, and AD in adults. Utilizing the UK Biobank dataset, we evaluated the impacts of FAs on the risk of elderly-onset AD and explored the combined effects of FA levels and genetic susceptibility. Plasma omega-3 levels exhibited an inverse correlation with AD risk (hazard ratio [HR]: 0.93
95% confidence interval [CI]: 0.89-0.98), regardless of genetic predisposition. Individuals with low genetic risk and high omega-3 levels had the lowest AD risk, a 38% reduction compared to the reference category. Additionally, individuals with GA/AA on rs1692120 exhibited a significantly elevated AD risk, whereas those with more A alleles for rs174448 demonstrated a significantly diminished AD risk (both p trends <
0.05). These findings suggest that increasing omega-3 intake could be a preventive strategy against AD, and tailoring prevention strategies based on genetic predispositions may enhance intervention efficacy.