Acute puromycin aminonucleoside (PA) nephrosis is associated with a surge in the glomerular macrophage number. Whole body X-irradiation (XI) was used to assess whether bone marrow depression, which depletes normal rat glomeruli of macrophages, is efficacious in ameliorating progressive glomerular disease. A solitary, sublethal dose of XI (600 rad) was administered 3 days after PA delivery to rats (PA/XI) that were followed for 18 wk. In contrast to a sham-irradiated nephrotic cohort (PA/Sham), the PA/XI rats had a complete prevention of the recurrent albuminuria and manifested a significant reduction in the percent of glomeruli exhibiting glomerulosclerosis (GS) lesions at 18 wk after PA. XI significantly reduced the glomerular and interstitial macrophage number as well as the circulating white blood and monocyte counts during peak albuminuria. This protection was independent of the magnitude of the acute albuminuria and elevations in the circulating lipid levels. These data show that whole body XI delivered during acute nephrosis is capable of preventing progressive glomerular disease in association with a reduction in the glomerular and interstitial macrophage number. Additionally, this study suggests that this immune effector cell is important in mediating the propagation of initial glomerular injury to GS.