Background Angiopoietin-like 3 (ANGPTL3)-deficiency due to loss-of-function variants are being reported to have a link with triglyceride (TG) level, and high-density lipoprotein cholesterol (HDL-C), and thereby affecting the risk of cardiovascular disease (CVD). Objective In the present study, we examined the association of rs10789117 in the ANGPTL 3 gene locus and the risk of CVD in the group of people who were part of the group of Mashhad-Stroke and Heart-Atherosclerotic-Disorders (MASHAD) cohort. Method 1002 cases with/without CVD following 10 years follow-up were recruited from the MASHAD cohort, followed by DNA extraction and genotyping. The association of the variant with CVD even and lipid profile was assessed using Univariate and Multivariate analysis. Result our data showed that CVD patients after 10 years follow up with AC/CC genotypes have been related to higher risk of CVD events compared to AA genotype (OR = 1.43, 95%CI = 1.01–2.02, P = 0.041) as well as its C allele with CVD risk (OR = 1.32, 95%CI = 1.06–1.72, P value = 0.038). Moreover, we realized that significant association between the variant and serum TG and HDL-C. Conclusion We demonstrated the potential value of g.14079A > C in ANGPTL3 in CVD, indicating further investigations of the emerging biomarker in a multi-center setting as a risk stratification biomarker in cardiovascular disease.