The goal of this study was to assess the use of quantitative single-photon emission computed tomography/computed tomography (SPECT/CT) analysis for vascularized volume measurements in the use of the yttrium-90-radiolabeled microspheres (TheraSphere). A phantom study was conducted for the validation of SPECT/CT volume measurement. SPECT/CT quantitative analysis was used for the measurement of the volume of distribution of the albumin macroaggregates (MAA; i.e., the vascularized volume) in the liver and the tumor, and the total activity contained in the liver and the tumor in four consecutive patients presenting with a complex liver vascularization referred for a treatment with TheraSphere. SPECT/CT volume measurement proved to be accurate (mean error <7%) and reproducible (interobserver concordance 0.99). For eight treatments, in cases of complex hepatic vascularization, the hepatic volumes based on angiography and CT led to a relative overestimation or underestimation of the vascularized hepatic volume by 43.2 ± 32.7% (5-87%) compared with SPECT/CT analyses. The vascularized liver volume taken into account calculated from SPECT/CT data, instead of angiography and CT data, results in modifying the activity injected for three treatments of eight. Moreover, quantitative analysis of SPECT/CT allows us to calculate the absorbed dose in the tumor and in the healthy liver, leading to doubling of the injected activity for one treatment of eight. MAA SPECT/CT is accurate for volume measurements. It provides a valuable contribution to the therapeutic planning of patients presenting with complex hepatic vascularization, in particular for calculating the vascularized liver volume, the activity to be injected and the absorbed doses. Studies should be conducted to assess the role of quantitative MAA/SPECT CT in therapeutic planning.