Based on superior image quality, more accurate gated images, and lower radiation exposure to patients, Technetium-99m (Tc-99m) based tracers are preferred over Thallium-201 for SPECT myocardial perfusion imaging. The two Tc-99m tracers, sestamibi and tetrofosmin, have many similar characteristics but there are differences in blood and liver clearance rates, as well as the recommended time after injection for imaging to achieve optimal image quality. Because published peer-reviewed studies examining optimal times between injection and imaging are limited, it can be difficult to identify evidence-based opportunities to optimize imaging protocols. Using systematic literature review methods, this study was designed to identify and consolidate the available evidence on the use of sestamibi compared to tetrofosmin for variable injection to imaging times in regard to test efficiency, including test length and re-scan rates, and image quality, including overall quality and cardiac to extra-cardiac ratios. The composite of this data shows that earlier imaging with tetrofosmin is equivalent to later imaging with sestamibi when assessing subjective image quality or when quantifying heart-to-extra-cardiac ratios. Image quality and heart-to-extra-cardiac ratios comparing early versus later imaging with tetrofosmin were comparable if not equivalent to each other. The equivalency of the imaging quality occurs with 15 minutes (on average) earlier imaging compared to sestamibi and 30 minutes compared to standard time tetrofosmin. The subjective findings of equivalent image quality are also shown with objective measurements of heart-to-extra-cardiac ratios. In this review, the significantly shorter injection-to-acquisition times with tetrofosmin compared to sestamibi resulted in better efficiency and less waiting times for patients; in addition, significantly higher re-scan rates with sestamibi compared to tetrofosmin due to hepatic activity contributed to better throughput with tetrofosmin. (J Nucl Cardiol 2020)