Rationale: Evaluation of alternative radionuclides for use in prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) is currently focusing on 161 Tb, which may provide advantages by emitting additional Auger and conversion electrons. In this pilot study, we present preliminary dosimetry data for [ 161 Tb]Tb-PSMA-617 RLT in a direct comparison with [ 177 Lu]Lu-PSMA-617. Method: Six patients with metastatic castration-resistant prostate cancer (mCRPC) underwent treatment with [ 177 Lu]Lu-PSMA-617 and subsequently - after inadequate response - with [ 161 Tb]Tb-PSMA-617. Whole-body planar and SPECT imaging-based dosimetry of organs at risk (kidneys and salivary glands) and tumor lesions were calculated using IDAC for 177 Lu and OLINDA/EXM for 161 Tb. The therapeutic index (TI) of mean tumor-absorbed doses over relevant organs at risk was calculated. Results: Mean absorbed doses to organs at risk of PSMA-RLT were slightly higher for [ 161 Tb]Tb-PSMA-617 compared to [ 177 Lu]Lu-PSMA-617 (kidneys: 0.643 ± 0.247 vs. 0.545 ± 0.231 Gy/GBq, factor 1.18; parotid gland: 0.367 ± 0.198 vs. 0.329 ± 0.180 Gy/GBq, factor 1.10), but markedly higher regarding tumor lesions (6.10 ± 6.59 vs 2.59 ± 3.30 Gy/GBq, factor 2.40, p < 0.001). Consequently, the mean TI was higher for [ 161 Tb]Tb-PSMA-617 compared to [ 177 Lu]Lu-PSMA-617 for both, the kidneys (11.54 ± 9.74 vs. 5.28 ± 5.13, p = 0.002) and the parotid gland (16.77 ± 13.10 vs. 12.51 ± 18.09, p = 0.008). Conclusion: In this intra-individual head-to-head pilot study, [ 161 Tb]Tb-PSMA-617 delivered higher tumor-absorbed doses and resulted in superior TI compared to [ 177 Lu]Lu-PSMA-617. This preliminary data support 161 Tb as a promising radionuclide for PSMA-RLT in mCRPC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)