OBJECTIVES: Although the Advisory Committee for Immunization Practices (ACIP) and other organizations recommend annual influenza vaccination for cardiovascular disease patients (CVD), the vaccination rate is low in this risk group. Economic assessment of vaccination will aid public officials plan campaigns to increase coverage. METHODS: We estimated using a Monte Carlo (probabilistic) spreadsheet-based decision tree, the cost-effectiveness of vaccination to prevent hospitalization and death in all 27.1 million CVD patients in the US. We then estimated the benefit-cost ratios (BCR) associated with hospitalization and death averted by increasing coverage rates by 10% in all adult CVD patients from the current rates of 45% and 65% (for ages < 65 years and ≥ 65 years, respectively). Finally, we estimated the BCR associated with reaching the healthy people 2020 goal of vaccinating 90% of person’s ≥ 65 years and 80% of adults’ <65 years. We obtained treatment cost data from Marketscan database (2005-2010) and  epidemiological data from the literature. We performed the analysis from the health care perspective including only cost associated with hospitalization and vaccination and reporting median cost values. RESULTS: Vaccination of all 27.1 million CVD patients’ would result in the following: 20,738 (S.D 48,387)) quality-adjusted life years (QALY) saved, $10,107 (95% CI: cost-savings (CS) to $70,554) / QALY saved, $31,563 (CI: CS to $151,900)/ hospitalization averted, and $76,588 (CI: CS to $534,658)/ premature death averted. The base case BCR is 0.52. A 10% increase in vaccination rate costing $41.2million (S.D $7.2 million) would result in hospitalization-related savings of $28 million (S.D. $165 million) (BCR = 0.68). Achieving healthy 2020 goal would cost $257 million (S.D. $45 million) and result in $ 216 million (S.D. $1.4 billion) hospitalization savings (BCR= 0.84). CONCLUSIONS: Increasing vaccination coverage rate among CVD patients will avert hospitalization and most likely deaths, but with variability in economic impact.