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Background: Significant hepatobiliary accumulation of technetium 99m-labeled cardiac perfusion agents has been shown to cause alterations in the apparent localization of the agents in the cardiac walls. A Monte Carlo study was conducted to investigate the hypothesis that the cardiac count changes are due to the inconsistencies in the projection data input to reconstruction, and that correction of the causes of these inconsistencies before reconstruction, or including knowledge of the physics underlying them in the reconstruction algorithm, would virtually eliminate these artifacts., Methods and Results: The SIMIND Monte Carlo package was used to simulate 64 x 64 pixel projection images at 128 angles of the three-dimensional mathematical cardiac-torso (MCAT) phantom. Simulations were made of (1) a point source in the liver, (2) cardiac activity only, and (3) hepatic activity only. The planar projections and reconstructed point spread functions (PSFs) of the point source in the liver were investigated to study the nature of the inconsistencies introduced into the projections by imaging, and how these affect the distribution of counts in the reconstructed slices. Bull's eye polar maps of the counts at the center of the left ventricular wall of filtered back-projection (FBP) and maximum-likelihood expectation-maximization (MLEM) reconstructions of projections with solely cardiac activity, and with cardiac activity plus hepatic activity scaled to have twice the cardiac concentration, were compared to determine the magnitude and location of apparent changes in cardiac activity when hepatic activity is present. Separate simulations were made to allow the investigation of stationary spatial resolution, distance-dependent spatial resolution, attenuation, and scatter. The point source projections showed significant inconsistencies as a function of projection angle with the largest effect being caused by attenuation. When consistent projections were simulated, no significant impact of hepatic activity on cardiac counts was noted with FBP, or 100 iterations of MLEM. With inconsistent projections, reconstruction of 180 degrees resulted in greater apparent cardiac count losses than did 360 degrees reconstruction for both FBP and MLEM. The incorporation of attenuation correction in MLEM reconstruction reduced the changes in cardiac counts to that seen in simulations in which attenuation was not included, but resulted in increased apparent localization of activity in the posterior wall of the left ventricle when scatter was present in the simulated images., Conclusions: The apparent alterations in cardiac counts when significant hepatic localization is present is due to the inconsistency of the projections inherent in imaging. Prior correction of these, or accounting for them in the reconstruction algorithm, will virtually eliminate them as causes of artifactual changes in localization. Attenuation correction and scatter correction are both required to overcome the major sources of apparent count changes in the heart associated with hepatic uptake.