The favorable decay characteristics of ¹⁶¹Tb attracted the interest of clinicians in using this novel radionuclide for radioligand therapy (RLT). ¹⁶¹Tb decays with a similar half-life to ¹⁷⁷Lu, but beyond the emission of β⁻-particles and γ-rays, ¹⁶¹Tb also emits conversion and Auger electrons, which may be particularly effective to eliminate micrometastases. The aim of this study was to compare the dosimetry and therapeutic efficacy of ¹⁶¹Tb and ¹⁷⁷Lu in tumor-bearing mice using SibuDAB and PSMA-I&T, which differ in their blood residence time and tumor uptake. Methods: [¹⁶¹Tb]Tb-SibuDAB and [¹⁶¹Tb]Tb-PSMA-I&T were evaluated in vitro and investigated in biodistribution, imaging, and therapy studies using PC-3 PIP tumor–bearing mice. The ¹⁷⁷Lu-labeled counterparts served for dose calculations and comparison of therapeutic efficacy. The tolerability of RLT in mice was monitored on the basis of body mass, blood plasma parameters, blood cell counts, and the histology of relevant organs and tissues. Results: The prostate-specific membrane antigen (PSMA)-targeting radioligands, irrespective of whether labeled with ¹⁶¹Tb or ¹⁷⁷Lu, showed similar in vitro data and comparable tissue distribution profiles. As a result of the albumin-binding properties, [¹⁶¹Tb]Tb/[¹⁷⁷Lu]Lu-SibuDAB had an enhanced blood residence time and higher tumor uptake (62%–69% injected activity per gram at 24 h after injection) than [¹⁶¹Tb]Tb/[¹⁷⁷Lu]Lu-PSMA-I&T (30%-35% injected activity per gram at 24 h after injection). [¹⁶¹Tb]Tb-SibuDAB inhibited tumor growth more effectively than [¹⁶¹Tb]Tb-PSMA-I&T, as can be ascribed to its 4-fold increased absorbed tumor dose. At any of the applied activities, the ¹⁶¹Tb-based radioligands were therapeutically more effective than their ¹⁷⁷Lu-labeled counterparts, as agreed with the approximately 40% increased tumor dose of ¹⁶¹Tb compared with that of ¹⁷⁷Lu. Under the given experimental conditions, no obvious adverse events were observed. Conclusion: The data of this study indicate the promising potential of ¹⁶¹Tb in combination with SibuDAB for RLT of prostate cancer. Future clinical studies using ¹⁶¹Tb-based RLT will shed light on a potential clinical benefit of ¹⁶¹Tb over ¹⁷⁷Lu.