Introduction: Considering that estradiol (E2) and n-3 polyunsaturated fatty acids (PUFAs) have roles in neurogenesis and in neurotransmission, we examined whether the association of PUFAs with incident depressive symptoms in postmenopausal women is modified by hormone therapy (HT) use or estrogen status. Methods: Women (N=1616) free of depressive symptoms at baseline (2000-2002) in the Multi-Ethnic Study of Atherosclerosis were classified by HT usage and quartiles of dietary eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and the sum EPA+DHA. Women with serum E-2= 16 or taking an antidepressant, first as a function of HT use and n-3 PUFA quartiles, and second, as a function of low E2 status and n-3 PUFA quartiles. Results: Among HT non- users, positive, graded relationships (p-trends <= 0.003) were found between PUFAs and incident depressive symptoms. Compared to the lowest quartile, the adjusted risk ratios (RRs) for the highest were 2.10, 2.39, and 2.04 for EPA, DHA, and EPA+ DHA, respectively. For HT users, no associations were seen. When analyses were run for E2 status, the RRs over quartiles of the PUFAs were positive and graded for low E2 women, but were null for High E2 women. Conclusions: Higher intakes of DHA and EPA were associated with higher risk of depressive symptoms in nonusers of HT, contrary to hypothesis. (C) 2016 Elsevier Ltd. All rights reserved.