OBJECTIVES: Drugs for smoking cessation are considered of great importance to the decline of this epidemic, as smoking is the largest preventable cause of death worldwide. This study aimed to evaluate the cost effectiveness of varenicline compared with bupropion and NRT (gum and patches) in the treatment of smoking population from São Paulo, Brazil’s city. METHODS: Effectiveness data of 6-months of treatment were evaluated from a sample of patients (504) in the outpatient smoking care of Instituto do Coraçãoem São Paulo-Brasil (InCor). Direct drug costs were extracted from the Health System Prices Database. A Decision Tree Model was used for the analysis of Cost Effectiveness (CE) and Incremental Cost-Effectiveness Ratio (ICER), considering varenicline monotherapy as standard. RESULTS: The CEs obtained were BRL 1.31, BRL 1.34, BRL 1.88, BRL 3.09 and BRL 1.98 billion in the use of varenicline monotherapy, varenicline associated with bupropion, bupropion associated with gum, bupropion associated with NRT (gum and patches) and NRT in gum and patches,respectively. The ICERs were BRL 1.66 billion, BRL 153 million and per patient of BRL 1,400 and BRL 138,41 for varenicline associated with bupropion and bupropion associated with gum respectively and ICERs for bupropion associated with NRT and isolated NRT respectively were BRL 1.65 billion and BRL 164 billion (dominant). CONCLUSIONS: According to the results, treatment with varenicline (monotherapy) is cost effective for all comparators and cost saving when compared to NRT and bupropion associated with NRT.