<p>To investigate dosimetry-derived tumor-to-perfused normal tissue ratio (T/N) and corresponding clinical outcomes of patients receiving yttrium-90 radioembolization with glass microspheres for tumors identified as hypovascular on arterial-phase cross-sectional imaging. Patients with hypovascular lesions undergoing ⁹⁰Y-RE at a single institution were included. Inclusion criteria were hypodense or hypoattenuating tumors relative to normal liver on arterial phase CT or MRI, excluding necrotic tumors. Pre-treatment planning mapping angiography 99mTc-MAA SPECT/CT was used for multi-compartment dosimetry for T/N estimation. The final cohort comprised 27 patients (median age 68, range 52–85 years), including 13 with Child-Pugh A cirrhosis, and ECOG status of 0 (<i>n</i> = 15), 1 (<i>n</i> = 11), and 2 (<i>n</i> = 1). Tumor types were hepatocellular carcinoma (<i>n</i> = 11), intrahepatic cholangiocarcinoma (<i>n</i> = 8), and liver metastases (<i>n</i> = 8). Treatment strategies included lobar (19%), lobar plus segmentectomy (22%), single segmentectomy (33%) and multiple segmentectomies (30%). The mean index tumor size was 5.7 ± 3.2&#xa0;cm. Mean tumor and perfused normal tissue doses were 480 ± 314&#xa0;Gy and 270 ± 138&#xa0;Gy, respectively. Median T/N ratio on planning SPECT/CT was 1.56 (range 0.28–4.79). Response assessments using mRECIST criteria for index lesions were complete response (41%), partial response (33%), stable disease (22%), and progressive disease (4%). Nine patients experienced Grade 1 adverse events (ALP, ALT, or AST serum markers) with no other adverse events. Calculated T/N ratios were greater than 1.00 for most patients with hypovascular tumors, indicating that tumor uptake of ⁹⁰Y may be greater than perceived from arterial-phase cross-sectional imaging. Post-treatment follow-up demonstrated favorable outcomes for this patient population.</p>