Background, To determine the influence of smoking on Tc-99m-labeled methoxyisobutylisonitrile (Tc-99m-MIBI) lung uptake during myocardial perfusion imaging, we examined 60 subjects with normal myocardial perfusion scans, normal coronary angiograms, and no evidence of left ventricular hypertrophy. Methods and Results, The subjects were divided into 2 groups: Group 1 subjects had smoking histories of at least 10 pack-years and Group 2 subjects were nonsmokers, 99mTc-MIBI lung to heart ratios (L/H ratios) from anterior planar images were obtained for all subjects during exercise and resting states. Tc-99m-MIBI L/H ratios in smokers were significantly higher than in nonsmokers in both exercise and resting states, However, no significant difference in L/H ratios was found between exercise and resting states in smokers and nonsmokers. In addition, no significant correlation was found between smoking pack-years and either rest or exercise L/H ratios. Conclusions. (9)9(m)Tc-MIBI L/H ratios in smokers are higher than in nonsmokers. This must be considered when Tc-99m-MIBI L/H ratios are used clinically.