- Background The negative predictive value of a normal myocardial perfusion image (MPI) for myocardial infarction or cardiac death is very high. However, it is unclear whether a normal MPI, reflecting non-compromised blood flow in the stable state, would have the same prognostic implications in smokers as in patients who do not smoke. Methods The incidence of total mortality, cardiovascular mortality, and myocardial infarction was evaluated in 11,812 subjects (14.6% of whom were current smokers at the time of the study) with a normal MPI study and no past history of coronary artery disease during the period 1997 to 2008. Results During an average follow-up of 72.4 ± 32.4 months the risk for an acute myocardial infarction in current smokers was approximately 50% higher than the corresponding risk in non-smokers, despite a younger average age. Cox proportional regression models show that current smoking was associated with an increased hazard rate for the composite endpoint below age 60 (HR = 2.09, 95%CI 1.43–3.07, p Conclusions In individuals below age 60, but not at older ages, current smoking is associated with increased short- and long-term risk of cardiac death and acute myocardial infarction even in subjects with a normal MPI.