The purpose of this study was to compare the difference in prescribed radiation activity between glass and resin yttrium-90 (Y) microspheres for radioembolization of unresectable hepatocellular carcinoma (HCC) or liver metastases at a tertiary care teaching institution. The authors performed a retrospective analysis on 126 patients with primary HCC and hepatic metastatic disease from extrahepatic primary cancers who underwent radioembolization with glass or resin particles between 2008 and 2013 at their institution. Radiation activity estimates for prescribed treatments, as well as for the alternate embolization particles, were calculated using commonly employed formulae for both glass and resin particles for all treatments. A total of 217 treatments were performed on 126 patients, with 136 (62.7%) using glass particles and 81 (37.3%) using resin particles. Forty-six (36.5%) patients had metastatic colorectal cancer (CRC), 51 (40.5%) had primary HCC, while 11 (8.7%) had neuroendocrine carcinoma, and 18 (14.3%) had metastases from other primary tumors. The average prescribed activity was 2.66 GBq for glass treatments and 1.06 GBq for resin treatments across all cancer types. When the alternative treatment activity was calculated, activities were projected to decrease by an average of 1.52 GBq per treatment if resin microspheres were used instead of glass microspheres (-52.5%), while activities were projected to increase by an average of 1.57 GBq per treatment if glass microspheres were used instead of resin microspheres (148.9%; p < 0.001). Similar results were seen within each malignancy type and all projected changes were statistically significant (p < 0.001). In conclusion, prescribed radiation activity for radioembolization of unresectable hepatic cancer was significantly lower for resin compared to glass microspheres.