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Background: The role of omega-3 fatty acid in multiple sclerosis (MS) susceptibility is unclear. Objective: To determine whether fish/seafood intake or genetic factors that regulate omega-3 fatty acids levels are associated with MS risk. Methods: We examined the association of fish and shrimp consumption and 13 tag single nucleotide polymorphisms (SNPs) in FADS1, FADS2, and ELOV2 with risk of MS in 1153 individuals from the MS Sunshine Study, a case-control study of incident MS or clinically isolated syndrome (CIS), recruited from Kaiser Permanente Southern California. Results: Consuming fish/seafood at least once a week or at least once a month with regular fish oil use was associated with 44% reduced odds of MS/CIS (adjusted OR = 0.56; 95% CI = 0.41–0.76; p = 0.0002) compared with consuming fish/seafood less than once a month and no fish oil supplementation. Two FADS2 SNPs (rs174611 and rs174618) were independently associated with a lower risk of MS (adjusted ORs = 0.74, 0.79, p = 0.0056, 0.0090, respectively). Association of FADS2 SNPs with MS risk was confirmed in an independent dataset. Conclusion: These findings suggest that omega-3 fatty acid intake may be an important modifiable risk factor for MS. This is consistent with the other known health benefits of fish consumption and complementary genetic studies supporting a key role for omega-3 regulation. [ABSTRACT FROM AUTHOR]