Introduction: Nicotine addiction has become one of the largest international health problems, increasing the risk of cardiovascular disease, cancers, and respiratory diseases. There are several treatments available for smoking cessation with the most common transdermal nicotine replacement and anti-depressants. However current treatments are only mildly efficacious and have side effects which lead to a decrease in their effectiveness. Additional treatments for smoking cessation with lower side effects are required. Methods: We examined the efficacy of Remotiv® (Hypericum perforatum Special Extract - ZE117) compared to Nicabate® CQ Nicotine Replacement Therapy (NRT) and combination ZE117/NRT for smoking cessation over a treatment time of 10 weeks. Given the different pharmacological profiles of Ze117 and NRT it was expected that a combination treatment would be most efficacious for smoking cessation than the other two treatments alone. Sixty smokers aged between 18 and 60 years were enrolled in the study. Smoking status was assessed using CO levels measured by the Bedfont Smokerlyzer (primary outcome measure). Secondary outcome measures of anxiety, DSMIV nicotine dependence and Fagerström craving and symptoms were also recorded. Results: A significant main effect of reduction in the number of smokers over the course of the study was observed although there were no significant differences between any of the treatment groups on this variable after 14 weeks. Conclusions: These results indicate that the three treatment options are equally efficacious for smoking cessation. Interestingly the Ze117 treatment significantly reduced the amount of craving over the treatment duration of the study compared to the other two treatments indicating a possible mechanism by which Ze117 may assist in smoking cessation.