During pre-therapy evaluation for yttrium-90 (Y-90) radioembolization, it is uncommon to find severe imaging discordance between hepatic angiography versus technetium-99m-macroaggregated albumin (Tc-99m-MAA) single photon emission computed tomography with integrated low-dose CT (SPECT/CT). The reasons for severe imaging discordance are unclear, and literature is scarce. We describe 3 patients with severe imaging discordance, whereby tumor angiographic contrast hypervascularity was markedly mismatched to the corresponding Tc-99m-MAA SPECT/CT, and its clinical impact. The incidence of severe imaging discordance at our institution was 4% (3 of 74 cases). We postulate that imaging discordance could be due to a combination of 3 factors: (1) different injection rates between soluble contrast molecules versus Tc-99m-MAA; (2) different arterial flow hemodynamics between soluble contrast molecules versus Tc-99m-MAA; (3) eccentric release position of Tc-99m-MAA due to microcatheter tip location, inadvertently selecting non-target microparticle trajectories. Tc-99m-MAA SPECT/CT more accurately represents hepatic microparticle biodistribution than soluble contrast hepatic angiography and should be a key criterion in patient selection for Y-90 radioembolization. Tc-99m-MAA SPECT/CT provides more information than planar scintigraphy to guide radiation planning and clinical decision making. Severe imaging discordance at pre-therapy evaluation is ominous and should be followed up by changes to the final vascular approach during Y-90 radioembolization.