Most studies support that saturated fatty acid replacement with polyunsaturated fatty acids (PUFAs) may reduce the risk of cardiovascular diseases (CVDs) and put emphasis on the effects of N-3 PUFAs. The reported relationships between N-6 PUFAs and CVD risks vary. We aimed to examine the associations between N-6 PUFA concentrations and CVD risks. In this community-based prospective cohort study on CVD-free patients at baseline (N = 1835, age: 60.6 ± 10.5 years, women: 44.5%), we measured the fatty acid concentrations in the blood using gas chromatography. Four hundred twenty-four participants developed CVDs during follow up. The total N-6 PUFA concentration was inversely associated with the CVD risk, with a 48% lower risk in the highest N-6 PUFA concentration quartile (hazard ratio = 0.52; P for trend <0.001). The estimated population attributable risk of N-6 PUFAs indicated that approximately 20.7% of CVD events would have been prevented if the plasma N-6 PUFA concentration had been higher than the median value. The total N-6 PUFA concentration presented the highest net reclassification improvement (NRI = 7.2%, P = 0.03) for predicting incident CVD. Further studies on N-6 PUFAs, diet habits, and their relationships with healthcare are warranted.