Background:Perturbed lipid metabolic pathways may play important roles in the development of cardiovascular disease (CVD). However, existing epidemiological studies have focused more on discovering individual lipid metabolites for CVD risk prediction rather than assessing metabolic pathways. Methods:This study included a subcohort of 787 participants and all 230 incident CVD cases from the PREDIMED trial. Applying a network-based analytical method, we identified lipid subnetworks and clusters from a global network of 200 lipid metabolites and linked these subnetworks/clusters to CVD risk. Results:Lipid metabolites with more double bonds clustered within one subnetwork, whereas lipid metabolites with fewer double bonds clustered within other subnetworks. We identified 10 lipid clusters that were divergently associated with CVD risk. The hazard ratios [HRs, 95% confidence interval (CI)] of CVD per a 1-standard deviation (SD) increment in cluster score were 1.39 (1.17-1.66) for the hydroxylated phosphatidylcholine (HPC) cluster and 1.24 (1.11-1.37) for a cluster that included diglycerides and a monoglyceride with stearic acyl chain. Every 1-SD increase in the score of cluster that included highly unsaturated phospholipids and cholesterol esters was associated with an HR for CVD of 0.81 (95% CI, 0.67-0.98). Despite a suggestion that MedDiet modified the association between a subnetwork that included most lipids with a high degree of unsaturation and CVD, changes in lipid subnetworks/clusters during the first-year follow-up were not significantly different between intervention groups. Conclusions:The degree of unsaturation was a major determinant of the architecture of lipid metabolic network. Lipid clusters that strongly predicted CVD risk, such as the HPC cluster, warrant further functional investigations.