Purpose <p>Radioligand therapy (RLT) targeting PSMA (prostate-specific membrane antigen) has transformed the treatment of metastatic castration-resistant prostate cancer (mCRPC). However, bone marrow depletion remains a common side effect, particularly in patients with extensive bone metastases or prior myelotoxic therapies. This study evaluated [^99mTc]Tc-antigranulocyte scintigraphy to assess bone marrow reserve to guide myelotoxic treatment decisions.</p> Methods <p>Ten mCRPC patients with extensive osseous tumor load on [¹⁸F]F-PSMA PET/CT underwent [^99mTc]Tc-antigranulocyte scintigraphy to assess bone marrow reserve and RLT eligibility (interval: 26.6 ± 18.5 days). Visual comparison of both modalities evaluated tumor-bone marrow overlap. Patients without significant co-localization received RLT ([¹⁷⁷Lu]Lu-PSMA or [²²⁵Ac]Ac-PSMA) with laboratory monitoring before and between the cycles.</p> Results <p>No significant co-localization between viable bone marrow and PSMA-positive metastases was observed in 9/10 (90.0%) patients. Two other patients were excluded from RLT due to contraindications. Of the remaining seven patients, 2/7 (28.6%) underwent subsequent [¹⁷⁷Lu]Lu-PSMA therapy, 2/7 (28.6%) [²²⁵Ac]Ac-PSMA therapy and 2/7 (28.6%) [²²⁵Ac]Ac-[¹⁷⁷Lu]Lu-PSMA therapy. 1/7 (14.3%) received a single cycle of [¹⁷⁷Lu]Lu-PSMA, which was then followed by [²²⁵Ac]Ac-PSMA therapy. Follow-up laboratory results showed no significant changes from baseline (<i>p</i> &gt; 0.05).</p> Conclusion <p>[^99mTc]Tc-antigranulocyte scintigraphy may support the assessment of bone marrow reserve in patients with extensive bone metastases. Spatial mismatch was associated with no significant myelotoxicity, whereas high congruence may increase the risk. No fixed thresholds currently exist; thus, this method should be regarded as a supplementary tool in complex cases and future studies are needed to define the critical bone marrow volume.</p>