Tc-99m macroaggregated albumin (MAA) hepatic perfusion study and hepatic angiography are routinely performed prior to yttrium-90 (Y-90) microsphere therapy for patients with hepatocellular carcinoma (HCC) or metastatic cancers to the liver. The purpose of this study was to examine the incidence of altered Tc-99m MAA distribution in these patients and to identify factors that are associated with these changes. A total of 176 Tc-99m MAA hepatic perfusion studies in 159 patients performed in preparation for Y-90 microsphere therapy were retrospectively reviewed. Abnormal findings were identified and correlated with diagnosis, infusion site, tumor volume, and tumor uptake by using bivariate statistical analysis. Abnormal Tc-99m MAA distribution on the hepatic perfusion imaging studies include excessive hepatopulmonary shunting with an elevated shunting fraction (>10%; n=23, 13%) and abnormal intra-abdominal visceral deposition in the GI tract, pancreas, spleen, and umbilical vein (n=19; 11%). Patients with a diagnosis of HCC showed higher incidence of abnormal hepatopulmonary shunting compared with other types of tumors (p<0.05). The incidence of abnormal intra-abdominal visceral deposition is higher with infusion into the left hepatic artery or proper hepatic artery/common hepatic artery compared with infusion into right hepatic artery (p<0.001). In 9 of 12 cases with abnormal deposition in the stomach, duodenum, or pancreas, the cause was identified upon reviewing angiography retrospectively and was subsequently corrected. In conclusion, the hepatic perfusion imaging study is an important imaging modality in preparation and guidance of Y-90 microsphere treatment.