In radioembolic therapy (RET) of hepatic malignancies using yttrium-90 (Y)-labeled resin microspheres, radiation protection is primarily concerned with avoiding contamination by radioactive spheres. However, as Y is bound to the microsphere surface by a potentially reversible ion-exchange process, the aim of this study was to assess the extent of the potential excreted activity in urine. After RET with Y-labeled resin-based microspheres, urinary excretion of free Y was prospectively analyzed in 51 interventions (n = 45 patients) by sampling urine over 48 h (two 24-h intervals) consecutively. The measured urinary concentration of Y, normalized to the administered microsphere activity, was a median of 58.5 kBq L GBq (range = 3.5-590.9 kBq L GBq) and 17.8 kBq L GBq (1.8-58.8 kBq L GBq) for the first and second 24-h periods after administration, respectively (p ≤ 0.0001, F = 28.4, result from ANOVA). The total excreted activity significantly decreased (p ≤ 0.0001) from a median of 72.5 kBq in the first 24-h period to a median of 22.1 kBq in the second 24-h period. Urinary excretion of free Y after resin-based RET occurs for a longer period and at a higher activity excretion than previously published, which has to be considered when patients are either hospitalized or return home after RET. Existing approaches for patient hospitalization, especially in temporary radiation protection areas, justified by the previously reported lower excretion rate, should be re-evaluated, and as a consequence, the current product safety information and handling recommendations for Y-labeled resin-based microspheres may need to be revised.