Objective: One quit attempt with varenicline has been found to be a cost-effective smoking cessation intervention. The purpose of this study was to analyze varenicline’s cost-effectiveness in patients who relapse during or after the first treatment. A comparison was made between re-treatment schema with varenicline and re-treatment schema with bupropion, NRT and unaided cessation, and treatment once with varenicline in a Finnish context. Methods: The two-quit version of BENESCO Markov model was used to follow a cohort of smokers making up to two quit attempts over a lifetime. The abstinence rates of the interventions were derived from a Cochrane review. Gender- and age-specific data on the incidence and prevalence of five smoking-related diseases were included in the model. Quality-adjusted life-years, total expected costs, and the lifetime cumulative incidence of smoking-related morbidities and mortality were the primary outcomes evaluated. Results: The study cohort comprised 116,533 smokers who were willing to make a quit attempt. In the lifetime simulation, re-treatment with varenicline yielded 6,150–20,250 extra quitters, depending on the comparator. Among these quitters it was possible to prevent 899–2,972 additional cases of smoking-related diseases, and 395–1,307 deaths attributable to smoking. Re-treatment with varenicline resulted in cost savings of up to 54.9 million Euros. Re-treatment with varenicline dominated all the other smoking cessation interventions used in the analysis. Sensitivity analysis supported the robustness of the base case results. Limitations: The analysis did not consider adverse events, and included only five major smoking-related diseases, which is a conservative approach, and probably leads to under-estimation of cost-effectiveness of cessation interventions. Furthermore, assumptions of constant relative risks for smoking-related diseases for each smoking status and the proxy values used as efficacy estimates of second quit attempts for other interventions than varenicline are limitations. Conclusions: A second quitting effort with varenicline is economically justifiable.