Objectives: We conducted a prospective observational longitudinal study to measure the impact of cigarette smoking on on-clopidogrel platelet reactivity (OPR). Background: Previous reports on smokers��� paradox have only been able to show an association between cigarette smoking and enhanced response to clopidogrel therapy. No study has shown reversal of enhanced clopidogrel response after smoking cessation. Methods: From the prospective CROSS-VERIFY cohort, 810 subjects with repeated measurement of OPR at least 1 month apart were analyzed. With smoking status ascertained at 2 time points, baseline and at follow-up, study subjects were categorized into never smokers (n=628), smoking quitters (n=77), and persistent smokers (n=105). Dependent variables included OPR measured by the VerifyNowTM assay and the percentage of subjects with high OPR (HOPR). Results: At baseline, current smokers showed significantly lower OPR with no significant differences in OPR between future quitters and future persistent smokers. While the mean OPR of never smokers and persistent smokers did not change significantly during the follow-up duration (p=0.311 and 0.275, respectively), the mean OPR of quitters increased significantly by 19 PRU (p=0.013). The frequency of HOPR showed similar results with an 8-10% increase in smoking quitters in contrast to no significant changes in never and persistent smokers. Both mean OPR and the frequency of HOPR showed a linear inverse relationship with the amount of smoking (p<0.001). Conclusions: Enhanced clopidogrel response in smokers, the so-called ���smokers��� paradox��� was reversed after smoking discontinuation, suggesting causal relationship in addition to previously reported association between smoking and enhanced clopidogrel response.