Serum fatty acids (FAs) have wide effects on metabolism: Serum saturated fatty acids (SFAs) increase triglyceride (TG) levels in plasma, whereas polyunsaturated fatty acids (PUFAs) reduce them. Traditionally, Eskimos have a high consumption of omega-3 fatty acids (ω3 FAs); but the Westernization of their food habits has increased their dietary SFAs, partly reflected in their serum concentrations. We studied the joint effect of serum SFAs and PUFAs on circulating levels of TGs in the presence of metabolic syndrome components. We included 212 men and 240 women (age, 47.9 ± 15.7 years; body mass index [BMI], 26.9 ± 5.3) from 4 villages located in Alaska for a cross-sectional study. Generalized linear models were used to build surface responses of TG as functions of SFAs and PUFAs measured in blood samples adjusting by sex, BMI, and village. The effects of individual FAs were assessed by multiple linear regression analysis, and partial correlations (r) were calculated. The most important predictors for TG levels were glucose tolerance (r = 0.116, P = .018) and BMI (r = 0.42, P < .001). Triglyceride concentration showed negative associations with 20:3ω6 (r = −0.16, P = .001), 20:4ω6 (r = −0.14, P = .005), 20:5ω3 (r = −0.17, P < .001), and 22:5ω3 (r = −0.26, P < .001), and positive associations with palmitic acid (r = 0.16, P < .001) and 18:3ω3 (r = 0.15, P < .001). The surface response analysis suggested that the effect of palmitic acid on TG is blunted in different degrees according to the PUFA chemical structure. The long-chain ω3, even in the presence of high levels of saturated fat, was associated with lower TG levels. Eicosapentaenoic acid (20:5ω3) had the strongest effect against palmitic acid on TG. The total FA showed moderate association with levels of TG, whereas SFA was positively associated and large-chain PUFA was negatively associated. The Westernized dietary habits among Eskimos are likely to change their metabolic profile and increase comorbidities related to metabolic disease.