Purpose <p>To evaluate the prognostic value of [¹⁸F]FAZA PET in predicting long-term clinical outcomes of critical limb-threatening ischemia (CLTI) patients undergoing endovascular revascularization.</p> Methods <p>This prospective pilot study received IRB and ethics committee approval. Patients who were planned to undergo revascularization were recruited. All patients underwent both dynamic and static [¹⁸F]FAZA PET at two different time points, before and after revascularization. After modelling, dynamic [¹⁸F]FAZA PET-derived parameters (including K₁, K₂, K₃, K₄, K_i, and total volume distribution [V_T]) were extracted from each scan, and delta parameters were calculated. Also, standardized uptake values were calculated from the static [¹⁸F]FAZA PET. Furthermore, ankle-brachial indices (ABIs) were measured before and after revascularization. Patients were followed up clinically. All major events were documented, and patients were classified into two groups accordingly: “sustained response” and “therapy failure”.</p> Results <p>From the 12 prospectively recruited patients (mean age = 69 years), five patients were diagnosed with therapy failure during follow-up. K₁ (<i>p</i> = 0.012) and ABI (<i>p</i> = 0.006) were significantly different in the post-angioplasty setting versus pre-angioplasty evaluations, being significantly lower and higher, respectively. In patients who experienced sustained clinical response, K₁ (<i>p</i> = 0.028; significantly lower after treatment), V_T (<i>p</i> = 0.018; significantly higher after treatment), and ABI (<i>p</i> = 0.028; significantly higher after treatment) were significantly different after angioplasty versus before angioplasty. In patients with therapy failure, only V_T (<i>p</i> = 0.043; significantly lower after treatment) was significantly different. Considering between-group differences, ΔV_T was significantly different between those who experienced sustained response versus those with therapy failure (<i>p</i> = 0.003).</p> Conclusion <p>Our findings could support the potential prognostic value of changes in dynamic [¹⁸F]FAZA’s initial volume distribution in the pre- versus post-revascularization setting. Unlike traditional measures, such as ABI, which show tissue’s macrovasculature patency, dynamic [¹⁸F]FAZA PET could capture tissue-level microcirculation by V_T mapping.</p>