Canine kidneys were biopsied at 2-week intervals from 3 to 13 weeks after a single 15-Gy dose of intraoperatively delivered 6 MeV electrons to determine the pathogenesis and dose-limiting tissue for radiation nephropathy. The data suggest that the dose and time after irradiation determine the dose-limiting tissue. The early functional survival of canine kidneys appeared to be dependent on parenchymal cell killing. Histologic changes in epithelial cells were seen as early as 3 weeks after irradiation. The parenchyma decreased to 50% of the preirradiation volume by 9 weeks but repopulated to near normal by 11 weeks. A second wave of depopulation, possibly due to perivascular fibrosis, was evident at 13 weeks. Previous investigators have demonstrated progressively extensive changes in renal vessels after irradiation. In this study, permanent vascular damage was seen at 3 weeks; however, most early changes in vessel walls proved to be temporary and probably resulted from atrophic vasoconstriction following parenchymal depopulation. Vessel dimensions returned to near normal as the parenchyma repopulated; however, a "histohematic barrier" created by progressively increasing perivascular fibrosis may cause a reduction in oxygen and nutrient support of the parenchyma and permanent loss of renal function.