Background: While smoking is a major modifiable risk factor for secondary prevention of myocardial infarction (MI), active smoking is common among patients hospitalized with acute MI. Recent studies suggest that nicotinic receptor variants, and specifically the high-risk CHRNA5 rs16969968 A allele, are associated with cessation failure among noncardiac patients. This study investigates the association between CHRNA5 rs16969968 and smoking cessation in patients hospitalized with acute MI. Methods: Using data from the TRIUMPH study, we ascertained smoking status at the time of index hospitalization for acute MI and 1 year after hospitalization. After adjusting for age and sex, we used logistic regression to model the association between smoking cessation and CHRNA5 rs16969968. Results: At index admission, 752 (Caucasian) subjects were active smokers and 699 were former smokers. Among these ever smokers, the A allele was associated with significantly decreased abstinence (45.0% abstinence for A allele carriers vs. 51.7% for GG homozygotes; OR = 0.70, 95% CI = 0.56-0.88, p =.0027). The A allele was also significantly associated with decreased abstinence at 1 year (69.1% abstinence for A allele carriers vs. 76.0% for GG homozygotes; OR = 0.70, 95% CI = 0.53-0.94, p =.0185). Conclusions: Among patients who have smoked and who are hospitalized with acute MI, the high-risk CHRNA5 allele was associated with lower likelihood of quitting before hospitalization and significantly less abstinence 1 year after hospitalization with MI. CHRNA5 rs16969968 genotype may therefore identify patients who would benefit from aggressive, personalized smoking cessation intervention.