To evaluate a novel 2D-perfusion angiography (2D-PA) technique allowing pro- and retrospective flow analysis based on a proximal reference region of interest (ROI) and distal target ROI in patients treated for peripheral arterial disease. 2D-PA allows quantifying blood flow by post-processing of digital subtraction angiography (DSA). 2D-PA was performed pre and post interventional treatment of peripheral arterial disease (PAD; n = 24; 13 angioplasties, 11 stents) in 21 patients (17 men, 72 ± 9y) with Fontaine stage IIB / III. Time-to-peak (TTP), peak density (PD) and area-under-the-curve (AUC) were calculated. Ratios reference/target ROI (TTP_OUTFLOW/TTP_INFLOW; PD_OUTFLOW/PD_INFLOW; AUC_OUTFLOW/AUC_INFLOW) were calculated and correlated to changes in the ankle-brachial-index (ABI). 2D-PA was technically feasible in all cases. A significant increase in ABI was seen after interventional treatment (+39%; p < 0.0001). ABI increase was accompanied by an increase of 36% of PD_OUTFLOW/PD_INFLOW (p < 0.0001), a 52% decrease of TTP_OUTFLOW/TTP_INFLOW (p = 0.0007) and a 69% increase of AUC_OUTFLOW/AUC_INFLOW (p < 0.0001). The difference of TTP pre- and post-intervention showed a correlation with the difference in ABI (r = −0.53, p = 0.0081). The other measured parameters failed to demonstrate significant correlation with improved ABI. The presented 2D-PA technique allows quantitative assessment of arterial flow before, during and after interventional treatment in PAD.