This series of case studies provides the first clinical experience with the fibroblast activation protein-a (FAP)-targeting radiopharmaceutical [¹⁷⁷Lu]Lu-RTX-2358 in patients with advanced solid tumors. Methods: Six patients with advanced FAP-expressing solid tumor malignancies and no standard treatment options remaining, underwent radiopharmaceutical therapy (RPT) with [¹⁷⁷Lu]Lu-RTX-2358. Biodistribution was monitored using whole-body planar and SPECT/CT imaging, and dosimetric parameters were calculated for critical organs, red marrow, and tumors. Adverse events were graded according to the Common Terminology Criteria for Adverse Events version 5.0. Preliminary antitumor effects were evaluated after 2 RPT cycles. Results: RPT with [¹⁷⁷Lu]Lu-RTX-2358 was tolerable with no dose-limiting toxicity. The mean red marrow absorbed dose was 0.131 6 0.044 Gy/GBq (range, 0.057-0.227 Gy/GBq). The mean kidney absorbed dose was 0.509 6 0.169 Gy/GBq (range, 0.272-0.893 Gy/GBq). The mean tumor absorbed dose varied across patients, rangingfrom0.346to2.70Gy/GBq. Tumor effective half-times ranged from 95.9 to 159.5 h. Disease stabilization was achieved in 4 patients; progressive disease occurred in 2 patients. Conclusion:[¹⁷⁷Lu]Lu-RTX-2358 demonstrated a manageable safety profile in a series of patients who were heavily pretreated for their disease. Given a promising therapeutic index as a result of prolonged retention in tumors and clearance from normal organs, further clinical evaluation is warranted.