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Myocardial perfusion imaging can be performed using SPECT or positron emission tomography (PET). SPECT has lower specificity than PET, largely as a result of attenuation artifacts; however, it is more widely available. The authors describe a study of the effect of sex and body weight on the incidence of SPECT attenuation artifacts using a retrospective comparison of Tl-201 SPECT and Rb PET.One hundred sixty-one persons (101 men, 60 women; 81 normal weight, 80 overweight) underwent Tl-201 SPECT and Rb PET. The incidence of observed perfusion defects was studied in territories of the three major coronary arteries. SPECT and PET results were also compared with those of angiography in a subset of 75 patients.One hundred fourteen defects were reported on Rb PET compared with 176 defects with Tl-201 SPECT. Excess Tl-201 SPECT defects occurred in male and female, normal-weight and overweight persons. The average specificity was 64% for Tl-201 SPECT and 84% for Rb PET, reflecting this difference.Attenuation artifacts in Tl-201 SPECT occur frequently and are not confined to easily identifiable subgroups of patients. Therefore, measures to improve specificity of SPECT (e.g., prone or gated imaging) or alternative imaging techniques such as PET have potential advantages for everyone, not simply for obese patients and women with large breasts. In addition, awareness of the prevalence of SPECT attenuation artifacts, in both sexes and all weight categories, may contribute to improved accuracy of interpretation.