In the present study, SibuDAB, an albumin-binding PSMA ligand, was investigated in combination with actinium-225 and the data were compared with those of [²²⁵Ac]Ac-PSMA-617. In vitro, [²²⁵Ac]Ac-SibuDAB and [²²⁵Ac]Ac-PSMA-617 showed similar tumor cell uptake and PSMA-binding affinities as their ¹⁷⁷Lu-labeled counterparts. The in vitro binding to serum albumin in mouse and human blood plasma, respectively, was 2.8-fold and 1.4-fold increased for [²²⁵Ac]Ac-SibuDAB as compared to [¹⁷⁷Lu]Lu-SibuDAB. In vivo, this characteristic was reflected by the longer retention of [²²⁵Ac]Ac-SibuDAB in the blood than previously seen for [¹⁷⁷Lu]Lu-SibuDAB. Similar to [²²⁵Ac]Ac-PSMA-617, [²²⁵Ac]Ac-SibuDAB was well tolerated at 30 kBq per mouse. Differences in blood cell counts were observed between treated mice and untreated controls, but no major variations were observed between values obtained for [²²⁵Ac]Ac-SibuDAB and [²²⁵Ac]Ac-PSMA-617. [²²⁵Ac]Ac-SibuDAB was considerably more effective to treat PSMA-positive tumor xenografts than [²²⁵Ac]Ac-PSMA-617. Only 5 kBq per mouse were sufficient to eradicate the tumors, whereas tumor regrowth was observed for mice treated with 5 kBq [²²⁵Ac]Ac-PSMA-617 and only one out of six mice survived until the end of the study. The enhanced therapeutic efficacy of [²²⁵Ac]Ac-SibuDAB as compared to that of [²²⁵Ac]Ac-PSMA-617 and reasonable safety data qualify this novel radioligand as a candidate for targeted α-therapy of prostate cancer.