Purpose To compare outcomes of yttrium-90 radioembolization performed with resin-based (90Y-resin) and glass-based (90Y-glass) microspheres in the treatment of hepatocellular carcinoma (HCC) with associated portal vein invasion. Materials and Methods A single-center retrospective review (January 2005-September 2014) identified 90 patients (90Y-resin, 21; 90Y-glass, 69) with HCC and ipsilateral portal vein thrombosis (PVT). Patients were stratified according to age, sex, ethnicity, Child-Pugh class, Eastern Cooperative Oncology Group status, α-fetoprotein > 400 ng/mL, extent of PVT, tumor burden, and sorafenib therapy. Outcome variables included clinical and laboratory toxicities (Common Terminology Criteria Adverse Events, Version 4.03), imaging response (modified Response Evaluation Criteria in Solid Tumors), time to progression (TTP), and overall survival (OS). Results Grade 3/4 bilirubin and aspartate aminotransferase toxicities developed at a 2.8-fold (95% confidence interval [CI], 1.3-6.1) and 2.6-fold (95% CI, 1.1-6.1) greater rate in the 90Y-resin group. The disease control rate was 37.5% in the 90Y-resin group and 54.5% in the 90Y-glass group (P =.39). The median (95% CI) TTP was 2.8 (1.9-4.3) months in the 90Y-resin group and 5.9 (4.2-9.1) months in the 90Y-glass group (P =.48). Median (95% CI) survival was 3.7 (2.3-6.0) months in the 90Y-resin group and 9.4 (7.6-15.0) months in the 90Y-glass group (hazard ratio, 2.6; 95% CI, 1.5-4.3, P <.001). Additional multivariate predictors of improved OS included age < 65 years, Eastern Cooperative Oncology Group status < 1, α-fetoprotein ≤ 400 ng/mL, and unilobar tumor distribution. Conclusions Imaging response of 90Y treatment in patients with HCC and PVT was not significantly different between 90Y-glass and 90Y-resin groups. Lower toxicity and improved OS were observed in the 90Y-glass group.