OBJECTIVES: Limited pharmaceutical options are available for smoking cessation interventions for smokers with a history of cardiovascular disease (CVD) in the Netherlands. The objective of our study was to assess the cost-effectiveness of varenicline versus nicotine replacement therapy (NRT) in such a population. METHODS: A lifetime horizon Markov model was developed to compare the cost-effectiveness of smoking cessation therapies from the health care provider perspective. Efficacy data (continuous abstinence rates) for each therapeutic option was obtained from an indirect comparison of available clinical trials. The population of smokers with cardiovascular disease was divided into three cohorts: those with a history of coronary heart disease (CHD), stroke and peripheral vascular disease (PVD). In the model, the cohorts are followed as they progress through potential disease states including CHD, stroke, PVD, COPD, mouth cancer and lung cancer. Transition probabilities depend on age (35-65, 65+), gender and smoking status (current, former or never smoker) allowing for variations in the patient populations. Following the Dutch pharmacoeconomic research guideline, costs and effect were discounted at 4% and 1.5%, respectively. Univariate and probabilistic sensitivity analyses were performed to assess the robustness of the results. RESULTS: The cost-effectiveness model showed a gain of 0.29 (95% CI: 0.19 - 0.40) QALY in individuals with varenicline therapy over NRT for a 57 year old person with CVD. Incremental costs associated with the smoking cessation program amounted to €67 whereas incremental costs associated with additional medical costs in the extra lifetime equalled €456 on average. In total, the incremental cost of varenicline therapy compared to NRT was €523 (€276 - €815). Corresponding incremental cost-effectiveness ratio was estimated at €1,817/QALY (€1171/QALY - €2440/QALY) for varenicline vs. nicotine replacement therapy. CONCLUSIONS: The model suggests that varenicline therapy in people with CVD is cost-effective and provides value-for-money compared to NRT.