Purpose <p>To evaluate the safety and feasibility of intra-arterial ¹⁷⁷Lu-PSMA-radioligand therapy (RLT) in patients with liver-dominant metastatic castration-resistant prostate cancer (mCRPC).</p> Materials and Methods <p>Patients received up to six cycles of ¹⁷⁷Lu-PSMA-RLT (median 7.4&#xa0;GBq) at six-week intervals. Intra-arterial administration in the hepatic artery was off-label and indicated for patients with high hepatic tumour burden. Primary endpoints were safety (clinical and biochemical adverse events) and procedural feasibility. Exploratory efficacy endpoints were prostate-specific antigen (PSA) response and imaging (PET) response.</p> Results <p>Four patients received 16 cycles (10 intra-arterial, six intravenous). All intra-arterial procedures were technically successful and without periprocedural complications. Toxicity was acceptable and comparable to intravenous treatment, comprising mainly grade 1–2 clinical events with occasional grade 3 biochemical abnormalities, and no grade 4–5 clinical toxicities were observed. PSA decreases occurred in two patients (decrease 24–99%), while two patients had increases. Imaging response was more profound for liver metastasis.</p> Conclusion <p>These preliminary findings suggest that intra-arterial ¹⁷⁷Lu-PSMA-RLT is feasible and safe in liver-dominant mCRPC. Prospective studies with dosimetry are warranted.</p> Graphical abstract <p></p>