BACKGROUND.: Novel interventions that protect against ischemia and reperfusion injury are needed to improve early graft function after kidney transplantation. Propofol, a widely used anesthetic, has proven an efficient membrane-targeted antioxidant and cytoprotective agent. METHODS.: The cytoprotective effects of propofol and its reaction intermediate dipropofol on hypothermic proximal tubular epithelial cells were compared with other phenolic antioxidants. For delivery of propofol into kidney grafts, a water-soluble cyclodextrin complex of propofol was prepared. The therapeutic effects of this propofol formulation were studied in a porcine autotransplantation model using 45 min of warm ischemia and 22 hr of hypothermic preservation. RESULTS.: Propofol and dipropofol effectively protected tubular cells from hypothermic injury in vitro. Delivery of propofol to porcine kidneys was achieved by adding the cyclodextrin complex of propofol to the preservation solution during machine perfusion. This preservation strategy significantly prevented lipid peroxidation and tended to attenuate the increase in renovascular resistance during the early reperfusion period after autologous kidney transplantation. The antioxidant effects of propofol were followed by a modest improvement in renal function in the first 10 days after transplantation. Treatment with propofol during organ preservation did not reduce neutrophil infiltration into the graft. CONCLUSION.: We consider propofol to be a promising renoprotective agent that may attenuate hypothermic and ischemic acute kidney injury in renal transplantation. The novel application of cyclodextrin carrier systems enabled delivery of the water-insoluble propofol to the graft during hypothermic preservation.