BACKGROUNDS: Smoking cessation medications have been shown to yield higher success rates and sustained abstinence when compared to unassisted quit attempts. Although unassisted smoking cessation is still common in Japan, various treatments, including nicotine replacement therapy (NRT) and varenicline, can be covered by the health insurance system. OBJECTIVES:  To compare the health and economic consequences in Japan of using pharmacotherapy to support smoking cessation with unassisted attempts and the current mix of strategies used. METHODS:  A discrete event simulation model was developed, which included multiple quit attempts and relapses. The risk of developing smoking-related diseases was estimated based on the duration of smoking abstinence. Data collected from a survey conducted in Japan was used to determine the interventions selected by smokers initiating a quit attempt, along with the time between multiple quit attempts. The analyses were conducted from healthcare payers' perspective, with supplemental analyses in which productivity losses due to smoking-related diseases were estimated. Time horizon was set to lifetime. RESULTS:  Using pharmacotherapy (NRT or varenicline) to support quit attempts proved to be dominant when compared with unassisted attempts or the current mix of strategies (most are unassisted). If varenicline is always  chosen as the first choice for a quit attempt,　it would save JPY 206,100 and prolong 0.08QALY per smoker over a lifetime horizon, compared to current mix of strategies. The greatest cost saving was observed for the smokers aged from 40 to <50 years. CONCLUSIONS:  Increased utilization of smoking cessation pharmacotherapy to support quit attempts is estimated to be cost-saving, as well as to improve health outcomes of the many smokers who want to quit.