The aim of this study was to compare the efficacy and safety of Vernonia cinerea Less. (Compositae) (VC) with placebo. A 24 week, randomized, single-blind, placebo-controlled, parallel trial was conducted at outpatient smoking cessation clinic at Thanyarak Institute, Pathumthani, Thailand. A 3-gram of crushed dried whole plant of VC was prepared in infusion tea bag. Sixty-four subjects were equally randomized to receive a 14-day VC tea taken three times daily or placebo. Primary outcomes were continuous abstinence rate (CAR) and the 7-day point prevalence abstinence rate (PAR) which were confirmed by urine cotinine. Adverse events and laboratory data were assessed at baseline and at clinic visits. Results showed that the 12-week CARs were 28.1% with VC versus 12.5% with placebo (p = 0.12). CARs through 24 weeks post-treatment were 18.8% with VC and 9.4% with placebo (p = 0.28). The 7-day PARs at week 12 were 43.8% with VC versus 21.9% with placebo (p = 0.06) and at week 24, 34.4% with VC versus 15.6% with placebo (p = 0.08). VC was well tolerated with no serious adverse events. As expected, the daily cost of VC ($0.30) was lower than that of daily bupropion ($2.42) and nicotine replacement therapy (gum and patch) ($2.72 - $3.65). CARs and PARs tended to be greater than in VC compared with the placebo over 24-week follow-up period, but this difference was not statistically significant. Our results show promise and suggest that VC may be of potential alternative treatment with cost savings for smoking cessation. Larger scaletrials are needed to verify the efficacy of VC.