OBJECTIVES: Long-chain omega-3 polyunsaturated fatty acids (LCω3PUFAs), selenium (Se) and mercury (Hg) are three important components in fish. The cardioprotective effect of LCω3PUFA intake has been recognized; however, the hypothesis that this benefit may be greatest with high Se and low Hg levels has not been investigated. DESIGN: A cohort of 4508 American adults aged 18-30, without hypertension at baseline in 1985, were enrolled. Six follow-ups were conducted at examinations in 1987, 1990, 1992, 1995, 2000 and 2005. Diet was assessed by a validated interviewer-administered quantitative food frequency questionnaire at exams in 1985, 1992 and 2005. Incident hypertension was defined as first occurrence at any follow-up examination of systolic blood pressure (BP) ≥ 140 mmHg, diastolic BP ≥ 90 mmHg or taking antihypertensive medication. Toenail clippings were collected in 1987, and Se and Hg levels were quantified by instrumental neutron-activation analysis. RESULT: Participants in the highest LCω3PUFA intake quartile had a significantly lower incidence of hypertension (hazard ratio: 0.65; 95% CI: 0.53-0.79; P(trend) < 0.01) compared to those in the lowest quartile after adjustment for potential confounders. Docosahexaenoic acid showed a greater inverse association than eicosapentaenoic acid. The inverse association of LCω3PUFA intake with hypertension appeared more pronounced at higher Se and lower Hg levels, although interaction tests were statistically nonsignificant. CONCLUSIONS: Our findings indicated that LCω3PUFA intake was inversely associated with incidence of hypertension. The prior hypothesis that the potential antihypertensive effect of LCω3PUFA intake varies depending on joint levels of Se and Hg received modest support and cannot be ruled out.