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Background: The role of n–6 (ω-6) polyunsaturated fatty acids (PUFAs) in type 2 diabetes (T2D) is inconclusive. In addition, little is known about how factors involved in PUFA metabolism, such as zinc, may affect the associations. Objectives: We investigated the associations of serum n–6 PUFAs and activities of enzymes involved in PUFA metabolism, Δ5 desaturase (D5D) and Δ6 desaturase (D6D), with T2D risk to determine whether serum zinc concentrations could modify these associations. Design: The study included 2189 men from the prospective Kuopio Ischaemic Heart Disease Risk Factor Study, aged 42–60 y and free of T2D at baseline in 1984–1989. T2D was assessed by selfadministered questionnaires, by fasting and 2-h oral-glucose-tolerance test blood glucose measurement at re-examination rounds 4, 11, and 20 y after baseline, and by record linkage to the hospital discharge registry and the reimbursement register on diabetes medication expenses. Multivariate-adjusted Cox proportional hazards regression models were used to analyze associations. Results: During the average follow-up of 19.3 y, 417 men developed T2D. Those with higher estimated D5D activity (extreme-quartile HR: 0.55; 95% CI: 0.41, 0.74; P-trend , 0.001) and higher concentrations of total n–6 PUFAs (HR: 0.54; 95% CI: 0.41, 0.73; P-trend , 0.001), linoleic acid (LA; HR: 0.52; 95% CI: 0.39, 0.70; P-trend , 0.001), and arachidonic acid (AA; HR: 0.62; 95% CI: 0.46, 0.85; P-trend = 0.007) had a lower risk and those with higher concentrations of g-linolenic acid (GLA; HR: 1.28; 95% CI: 0.98, 1.68; P = 0.021) and dihomog- linolenic acid (DGLA; HR: 1.38; 95% CI: 1.04, 1.84; P-trend = 0.005) and higher D6D activity had a higher (HR: 1.50; 95% CI: 1.14, 1.97; P-trend , 0.001) multivariate-adjusted risk of T2D. Zinc mainly modified the association with GLA on T2D risk, with a higher risk observed among those with serum zinc concentrations above the median (P-interaction = 0.04). Conclusions: Higher serum total n–6 PUFA, LA, and AA concentrations and estimated D5D activity were associated with a lower risk of incident T2D, and higher GLA and DGLA concentrations and estimated D6D activity were associated with a higher risk. In addition, a higher serum zinc concentration modified the association of GLA on the risk of T2D. [ABSTRACT FROM AUTHOR]