OBJECTIVES: Despite well documented harm to both the mother and the fetus, maternal smoking during pregnancy continues to hover above 15%.  While pharmaceutical interventions have been shown to be cost-effective in the general population, current treatment options are poorly understood, insufficiently utilized and insufficiently effective in pregnant women.  No data regarding safety or efficacy of varenicline has been reported for this population.  To determine if clinical study of varenicline for pregnant smokers is warranted, a cost-benefit analysis of varenicline compared to existing treatment modalities will determine if there is likely any cost-benefit associated with varenicline use in this population. METHODS: A decision analysis model was developed to evaluate from the payer’s perspective the optimal treatment from the standpoint of cost versus benefit of potential treatment with varenicline compared to other smoking cessation treatment options in pregnant smokers.  Outcomes included smoking cessation rates, cost of maternal and infant outcomes associated with smoking, and treatment costs.  A sensitivity analysis was performed to determine the effects of variations in the success of treatment with varenicline. RESULTS: The analysis showed that buproprion is more cost-beneficial than the other treatments, with a net benefit of $1086 per pregnant smoker who attempts to quit, compared with $316 for usual care, $550 for motivational interviewing, $830 for NRT, and $938 for varenicline.  Sensitivity analyses indicate that at a 25% cessation rate, varenicline becomes the most cost-beneficial treatment option.   CONCLUSIONS: From a payer’s perspective and current knowledge of cessation rates with pregnant smokers, buproprion is more cost-beneficial smoking cessation intervention in pregnant women than existing treatment options.  If pregnant smokers are more successful than non-pregnant smokers at quitting on varenicline, as they are with the other cessation treatments, it is likely that varenicline is the most cost-beneficial treatment and may warrant additional study in this population.