Abstract Purpose To evaluate injury to normal liver parenchyma following radioembolization with yttrium-90 ( 90Y) resin microspheres as reflected by liver and spleen volume and liver function, and to investigate the influence of chemotherapy on these changes. Materials and Methods A retrospective review of a prospectively acquired database of patients undergoing 90Y radioembolization with resin microspheres over a 24-month period was performed to assess for changes in liver and spleen volume and liver function. Patients undergoing whole-liver or sequential bilobar treatment with at least 3 months of follow-up were included in the study. Chemotherapy records were reviewed, and the influence of agents with known hepatotoxicity on liver and spleen volume and alteration in liver function was assessed. Results Thirty-seven patients were included in the analysis. Significant decrease in liver volume (12.5%; P = .002) and increase in spleen volume (63%; P = .003) were observed, as were trends for increases in serum bilirubin, aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase levels and decreases in platelet and white blood cell counts. Chemotherapy with agents with known hepatotoxicity administered before and after radioembolization increased the extent of liver injury, but this did not reach statistical significance. Conclusions The normal liver is not spared radiation effects from 90Y radioembolization as demonstrated by serial changes in liver and spleen volumes, as well as liver function. However, these changes were of limited clinical significance in the patients studied.