Purpose: Severe Omega-3 (OM3) nutritional deficiency has been previously correlated to an increased of sudden death and based upon plasma OM3 levels, risk quartiles have been defined. However, studies that monitor the correction of OM3 deficiency (measured as Omega-Score, OS) with treatment with an OM3 formulation, and improvement of Cardiovascular Disease (CVD) factors have not been systematically evaluated. The purpose of this study was to determine the extent of OM3 deficiency in the general and CVD populace and to investigate how treatment with a unique OM3 formulation comprised of >90% pure OM3, with a 6:1 EPA: DHA ratio (eicosapentaenoic acid: docosapentaenoic acid, 6:1-OM3) corrects this deficiency, and improves CVD factors. Methods: The primary endpoints of this randomized, double blind, placebo-controlled trial were the change in the OS (plasma EPA + DHA + docosapentaenoic acid) with secondary endpoints including the change in serum TG, lipoprotein cholesterol (VLDL, LDL, HDL, ApoB, and subfractions), and hsCRP. 655 subjects were screened, and 110 subjects that met all study criteria (including OS <6.1%) were randomized and stratified by baseline TG levels (Cohort 1: 90-199 mg/dL, and Cohort 2: 200-500mg/dL). Treatment included placebo (4g/day corn oil, n=54) and 6:1-OM3 (4g/day; n=56) for an 8-week study period. Results: 89% of screened (n=655) CVD subjects were found to be nutritionally deficient in OM3 (OS <6.1%). The median baseline OS was 3.64% for Cohort 1, and 3.15% for Cohort 2. After 8 weeks of treatment, a significant (p<0.0001) increase was observed for both Cohorts, resulting in an OS increase of 134% for Cohort 1 and 120% for Cohort 2. In normal and mildly hypertriglyceridemic subjects (90-199 mg TG/dL), no significant changes in lipid profiles were observed. However in moderately hypertriglyceridemic subjects (200-500 mg TG/dL), a placebo-corrected TG reduction of 48% (p=0.0005), VLDL-C reduction of 30% (p=0.0023) and HDL-C increase of 9% (p=0.0069) without significantly affecting LDL-C, ApoB or hsCRP levels was observed. Conclusions: This study confirms that OM3 deficiency is highly prevalent in patients with CVD. In patients with moderate hypertriglyceridemia, treatment with 6:1-OM3 corrects the deficiency and results in a concomitant and significant placebo-corrected reduction in TG and VLDL, and increase in HDL-C without adversely affecting LDL-C.