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Background: Two-dimensional (2D) perfusion angiography is useful for the evaluation of foot perfusion in patients with critical limb-threatening ischemia (CLTI). Iloprost is a synthetic prostacyclin analogue presenting vasodilating properties. Aim of this study was to demonstrate the utility of 2D perfusion angiography as quantitative method to evaluate iloprost effect on foot circulation. Patients and methods: Between January 2020 and June 2020 25 patients with CLTI underwent below-the-knee (BTK) endovascular revascularization, intra-arterial administration of iloprost, and assessment of foot perfusion by 2D perfusion angiography. Iloprost was administered as an intra-arterial bolus of 3 μg over 1-3 minutes immediately after BTK revascularization. The 2D perfusion angiography was performed in a standardized manner with a 5-F catheter placed into the popliteal artery. A wide region of interest (ROI) was identified to assess the foot perfusion. Time-density curves were calculated by the perfusion software. Changes of the overall time-density curves before and after the administration of iloprost were evaluated. Results: Endovascular revascularization was successful in all cases. The mean reduction of systolic pressure value after iloprost administration was 23.1 mmHg. Eight patients (32%) experienced a minor complication (6 cutaneous rush, 2 symptomatic hypotension >40 mmHg). In 20 patients the time-density curves under ROI increased after the intra-arterial administration of iloprost (+31.6%, range from +4.9% to +78.7%). Five patients had no modification or a slight decrease of foot perfusion after iloprost administration (non-responders patients). Conclusions: Patients undergoing intra-arterial administration of iloprost accounted for a not negligible rate of minor complications. 2D perfusion angiography was valuable as quantitative method to evaluate the iloprost effect on foot circulation. This technique could be useful to classify the patients in responders or non-responders to iloprost therapy.