Background: Late-outgrowth endothelial progenitor cells (LEPC) are a potential autologous cell source for cardiovascular therapeutics; however, progenitor function is impaired in potential target groups. We aimed to assess if LEPC dysfunction can be reversed by normalising molecular differences relevant to angiogenesis. Methods: Analysis of in vitro LEPC function (migration, angiogenesis) was performed in 12 South Asian (SA) men and 12 matched white European (WE) controls. Western blotting was used to assess Akt and eNOS abundance. LEPC were transfused into CD1 immunodeficient mice subsequent to angioplasty wire induced femoral artery luminal injury, or femoral artery ligation induced limb ischaemia, to assess in vivo reparative function. In vitro and in vivo studies were repeated after lentiviral gene delivery of constitutively active Akt1 (E17K) or control (EGFP) to SA LEPC. Data are expressed as mean [standard error of mean]; p<0.05 by t-test is denoted by *. Results: Age and cardiovascular risk factors were comparable in the 2 groups, although the SA group was relatively insulin resistant (HOMA-IR 1.2[0.2] vs. 0.5[0.1] au*). SA LEPC exhibited impaired VEGF induced migration (5[0.7] vs. 10[1.7] LEPC/microscope field*) and in vitro angiogenesis (1.9[0.6] vs. 3.8[0.5] tubular structures/microscope field*), associated with decreased abundance of the phosphorylated forms of S473-Akt1 (0.14[0.05] vs. 0.81[0.2] au*) and S1177-eNOS (0.05[0.02] vs. 0.15[0.01] au*). Transfusion of WE LEPC into immunodeficient mice after femoral artery injury augmented re-endothelialisation; however, neither SA LEPC, nor vehicle, augmented re-endothelialisation (WE: 54.2 [6.4], SA: 36.9 [3.4], vehicle: 31.1 [2.4] % re-endothelialised [absent Evans blue stain]; WE vs. SA*). Whilst control LEPC promoted perfusion recovery after induction of hind limb ischemia, neither SA LEPC nor vehicle did (WE: 66.4 [4.7], SA: 49.3 [5.6], vehicle: 50.6 [2.8] % ischaemic/non-ischaemic limb flux [Laser Doppler]; WE vs. SA*). Lentiviral gene delivery of E17KAkt, but not EGFP control, to SA LEPC was associated with augmented Akt1 activity. Expression of E17KAkt in SA LEPC rescued in vivo re-endothelialisation capacity (E17K: 55.2 [4.4] vs. EGFP 24.1 [1.3] % re-endothelialised; E17K vs. EGFP*; E17K vs. WE non-transduced cells p=0.9). Furthermore, E17KAkt expressing SA LEPC exhibited markedly augmented limb perfusion after femoral artery ligation, in contrast with EGFP control (E17K: 63.4 [2.4] vs. EGFP 48.0 [1.6] % ischaemic/non-ischaemic limb flux; E17K vs. EGFP*; E17K vs. WE non-transduced cells p=0.9). Conclusions: These data provide proof of principle for human LEPC based vascular repair therapy, and provide a mechanism by which function of LEPC from insulin resistant humans can be restored.