This study presents the first-in-human SPECT/CT imaging using $ {}^{212} $ Pb-PSMA-targeted α-therapy in a patient with metastatic castration-resistant prostate cancer (mCRPC). The patient received 60 MBq of $ {}^{212} $ Pb-ADVCO001, and SPECT/CT images were acquired at 1.5, 5, 20, and 28 hours post-infusion. The images were obtained using a Siemens Intevo Bold scanner with two simultaneous triple-energy window acquisitions. The study was approved by the local institutional review board. The $ {}^{212} $ Pb SPECT/CT images showed rapid tumor uptake of $ {}^{212} $ Pb-ADVCO001, which was highly concordant with tumor burden delineated on the pretreatment $ {}^{18} $ F-DCFPyl PET/CT images. At 20 hours post-infusion, tumor uptake was still evident despite the high decay rate of $ {}^{212} $ Pb (half-life of 10.6 hours). The images demonstrated the feasibility of $ {}^{212} $ Pb SPECT/CT imaging in providing postinfusion radiopharmaceutical biodistribution and patient-specific dosimetry for clinical development of $ {}^{212} $ Pb-targeted α-therapy. The study highlights the challenges of imaging $ {}^{212} $ Pb due to high-energy γ-rays from the lead progeny, which generate Compton scatter. The approach of summing images reconstructed from both energy windows showed the feasibility and benefit of $ {}^{212} $ Pb SPECT/CT imaging. This work was financially supported by AdvanCell through the TheraPb clinical trial (NCT05720130). The authors disclose potential conflicts of interest related to their affiliations with AdvanCell. The study acknowledges the clinical staff at the Princess Alexandra Hospital.This study presents the first-in-human SPECT/CT imaging using $ {}^{212} $ Pb-PSMA-targeted α-therapy in a patient with metastatic castration-resistant prostate cancer (mCRPC). The patient received 60 MBq of $ {}^{212} $ Pb-ADVCO001, and SPECT/CT images were acquired at 1.5, 5, 20, and 28 hours post-infusion. The images were obtained using a Siemens Intevo Bold scanner with two simultaneous triple-energy window acquisitions. The study was approved by the local institutional review board. The $ {}^{212} $ Pb SPECT/CT images showed rapid tumor uptake of $ {}^{212} $ Pb-ADVCO001, which was highly concordant with tumor burden delineated on the pretreatment $ {}^{18} $ F-DCFPyl PET/CT images. At 20 hours post-infusion, tumor uptake was still evident despite the high decay rate of $ {}^{212} $ Pb (half-life of 10.6 hours). The images demonstrated the feasibility of $ {}^{212} $ Pb SPECT/CT imaging in providing postinfusion radiopharmaceutical biodistribution and patient-specific dosimetry for clinical development of $ {}^{212} $ Pb-targeted α-therapy. The study highlights the challenges of imaging $ {}^{212} $ Pb due to high-energy γ-rays from the lead progeny, which generate Compton scatter. The approach of summing images reconstructed from both energy windows showed the feasibility and benefit of $ {}^{212} $ Pb SPECT/CT imaging. This work was financially supported by AdvanCell through the TheraPb clinical trial (NCT05720130). The authors disclose potential conflicts of interest related to their affiliations with AdvanCell. The study acknowledges the clinical staff at the Princess Alexandra Hospital.