High-sensitivity C-reactive protein (CRP) has been extensively used in recent years to assess cardiovascular risk more thoroughly. A significant association between elevated CRP, a prevalence of coronary artery disease (CAD) and adverse cardiac events has been found. Stress myocardial SPECT perfusion imaging (MPI) is an accurate noninvasive technique for detecting CAD. The aim of our study was to find out if there are any differences in the CRP levels between patients with normal myocardial perfusion and mild to moderate perfusion defects, detected with 99m-Tc sestamibi gated SPECT MPI. We prospectively studied 127 patients (79 men, 48 women) suspected of having CAD or with previously confirmed CAD, who were referred for MPI. According to the findings of the stress study, they were divided into two groups: with normal/ near normal myocardial perfusion (n = 85) and with a mild to moderate perfusion defect (n = 42). Levels of CRP in the former group were significantly lower (2.7 mg/L vs. 4.2 mg/L, p = 0.01). There were significantly more men (78.6% vs. 54%, p = 0.000*) and smokers (26% vs. 15%, p = 0.003), also the rates of PCI were significantly higher (36% vs. 15%, p = 0.006) in patients with mild to moderate perfusion defects. The two groups did not differ significantly in age, type of stress, presence of most risk factors for CAD, previous myocardial infarction and CABG. The results of our study have shown that patients with mild to moderate perfusion defects on stress myocardial perfusion SPECT imaging have significantly higher levels of C-reactive protein, compared to those with normal/near normal myocardial perfusion.