Purpose Triglycerides are considered an emerging risk factor for cardiovascular mortality. Recent evidence relating depression and metabolic syndrome (MetS) implicated triglyceride levels. We thus investigated interrelations of self-reported depression severity (Zung) and MetS-related biological measures with CVD risk estimates in MetS patients. Methods N = 101 patients fulfilling International Diabetes Federation criteria for MetS from a nationwide sampled treatment cohort for MetS with familial T2DM risk or manifest T2DM in a Ukrainian governmental health care system were participants. Both laboratory and non-laboratory measures were included. Recent European cardiological SCORE system CVD risk estimates were used as outcome variables. Results Following correlation matrix, we entered all variables into principal component analysis (PCA; 76.7% explained variance), followed by hierarchical regression and structural equation modeling (SEM). The PCA suggested a one-factor solution, where the latent variable showed highest loadings of SCORE risk estimates, triglycerides, depression severity, and pulse pressure. A comprehensive SEM was adjusted with 92.7% explained variance: overall CVD risk related to depression, pulse pressure, triglycerides, and fasting glucose. Conclusion The findings in this MetS sample suggest that triglycerides and depression severity are the key variables among MetS biomarkers in cross-sectionally associating with the fatal and total SCORE risk estimates in MetS.