The chemokine receptor CXC-chemokine receptor 4 (CXCR4) is a transmembrane receptor involved in survival, proliferation, and dissemination of different cancers, including hematopoietic malignancies. Relapsed or refractory hematopoietic cancers are frequently resistant to conventional therapy, and novel highly active strategies are urgently needed. CXCR4-directed endoradiotherapy constitutes a highly promising targeted therapeutic concept. Here, we investigated the adverse effects of this novel treatment approach. Twenty-two patients with heavily pretreated lymphoproliferative or myeloid malignancies were treated with ¹⁷⁷Lu- or ⁹⁰Y-pentixather—a CXCR4-directed therapeutic radioligand—before conventional conditioning therapy followed by autologous or allogeneic hematopoietic stem cell transplantation. Twenty-five CXCR4-directed endoradiotherapies were administered to those patients. Adverse events occurring between endoradiotherapy and the start of conventional conditioning therapy were retrospectively analyzed and graded for the estimation of the safety profile. CXCR4-directed endoradiotherapy with pentixather showed a favorable toxicity profile. As expected, the hematopoietic system was most affected, with all subjects developing cytopenias. Except for 1 acute kidney failure, grade 3, due to tumor lysis syndrome, overall nephro- and hepatotoxicity was low. Other higher-grade adverse events were either transient and resolved or easily manageable. Therapy with radiolabeled pentixather appears to be well tolerated and easily applicable when preceding conventional conditioning regimens for hematopoietic stem cell transplantation.