The performance of SPECT myocardial perfusion imaging (MPI) may deteriorate in smaller hearts, primarily because of the lower resolution of conventional Anger cameras. F-flurpiridaz is a novel PET MPI agent with superior image and defect resolution. We sought to determine the diagnostic performance of Tc-labeled SPECT MPI compared with F-flurpiridaz PET MPI according to left ventricle (LV) size. We conducted a substudy of the phase III clinical trial of flurpiridaz ( = 750) and stratified diagnostic performance according to the median PET LV end-diastolic volume (LVEDV), with smaller LVs defined as having an LVEDV of less than 113 mL ( = 369) and larger LVs defined as having an LVEDV of at least 113 mL ( = 381). Images were interpreted by the majority rule of 3 independent masked readers. The reference standard was quantitative invasive angiography, with at least 50% stenosis in at least 1 coronary artery considered significant. SPECT performance decreased significantly from an area under the curve (AUC) of 0.75 in larger LVs to 0.67 in smaller LVs ( = 0.03), whereas PET performance was similar in larger and smaller LVs (AUC, 0.79 vs. 0.77, = 0.49). Accordingly, in smaller LVs, PET had a higher AUC (0.77) than the SPECT AUC (0.67) ( < 0.0001), a phenomenon driven by female patients ( < 0.0001). In smaller LVs, there was a degradation of SPECT sensitivity that was highly significant ( < 0.001), whereas there was no significant change in PET sensitivity according to LV size ( = 0.07). Overall, PET had significantly higher sensitivity than SPECT in both smaller LVs (67% vs. 43%, < 0.001) and larger LVs (76% vs. 61%, < 0.001). The specificities of PET and SPECT were similar in larger LVs (76% vs. 83%, = 0.11). Although SPECT specificity improved in smaller compared with larger LVs (90% vs. 83%, = 0.03), the PET specificity did not change with LV size (76% vs. 76%, = 0.9). The diagnostic performance of F-flurpiridaz PET MPI is not affected by LV size and is superior to SPECT MPI in patients with smaller LVs, highlighting the importance of appropriate test selection in these patients.