OBJECTIVES: Varenicline and bupropion are commonly recommended pharmacotherapies for smoking cessation. Post marketing reports suggest that bupropion and varenicline are associated with an increased incidence of psychiatric disturbances. However, pre-existing psychiatric conditions and lack of cigarettes (nicotine) confound the association between smoking cessation agents (SCA) and psychiatric disturbances. The aim of the study was to determine the impact of SCA on the mental health status.  METHODS: Data were from the 2006-2010 Medical Expenditure Panel Survey. Adults with new episodes of varenicline or bupropion, defined as current use of one of these agents without prior use of any SCA agents in the previous round, were identified.  The main outcome was the mental component summary (MCS) scores derived from the mental health component of SF-12v2. The MCS scores of SGA agent users were compared to that of current smokers and adults who quit smoking without any SCA use. Linear regression was used to adjust for sociodemographic characteristics, pre-existing psychiatric conditions, and medical comorbidities.  RESULTS: There were 117 new episodes of varenicline use, 426 new episodes of bupropion use, 1138 subjects who quit smoking without any SCA and 9178 current smokers. Compared to current smokers, varenicline use was associated with a statistically as well as clinically insignificant change in the MCS score (0.20) [p>0.05] while bupropion use was associated with a significant decrease in the MCS score (-4.18) [p<0.01]. Subjects who quit smoking with any SCA use were associated with a clinically insignificant increase in the MCS score (1.39) [p<0.01]. The presence of pre-existing psychiatric conditions was associated with a significant decrease in the MCS score [-4.33] (p<0.01). CONCLUSIONS: Varenicline is associated with an insignificant change in mental health status, compared with current smokers. The study supports the use of varenicline as first line therapy for smoking cessation.