Experimental galactosemia, induced by feeding rats a galactose enriched diet, reproduces many of the neural and ocular complications of diabetes and induces protein glycation and polyol accumulation. To explore the role of these biochemical abnormalities in the pathogenesis of glomerular injury, adult male Sprague-Dawley rats were placed on either a 50% galactose or 50% glucose diet. After two months, galactose fed rats exhibited elevated excretory rates of protein, albumin, and IgG. Blebbing and ballooning of the glomerular epithelial cells were apparent in rats on the galactose supplemented diet. Morphometric evaluation of the glomeruli revealed an increase in the fractional and absolute volume of the glomerular epithelial cells, but glomerular and mesangial volume, basement membrane thickness, and epithelial foot process width were similar on the two diets. Glycation of the glomerular basement membrane was increased in the galactose fed rats. Glomerular micropuncture revealed similar glomerular pressures and flow rates on the two diets. Aldose reductase inhibition had no effect on galactose induced proteinuria. These results suggest that biochemical abnormalities such as protein glycation may be important in the pathogenesis of altered glomerular permselectivity in diabetic nephropathy.