Increasing evidence from experimental models of chronic renal failure suggests that abnormalities in lipid metabolism may contribute to progressive renal injury. In the present study, hyperlipidemic obese, and normolipemic lean Zucker rats were subjected to unilateral nephrectomy or sham surgery at eight weeks of age. After 32 weeks, renal injury was greater in obese than in lean rats, and injury was made worse by nephrectomy. Among the major lipid classes, increased renal cortical cholesteryl esters were positively correlated with the degree of renal injury, suggesting that mechanisms analogous to those thought to be important in the pathogenesis of atherosclerosis may cause renal injury. Among phospholipid fatty acids, the ratio of oleic to linoleic acids (18:1/18:2) was strongly linked to both glomerular (r = 0.83, P < 0.01) and tubulo-interstitial (r = 0.80, P < 0.01) injury, suggesting a possible role for a relative essential fatty acid deficiency in renal injury. There were also strong, negative associations between eicosapentaenoic acid levels and glomerular (r = -0.63, P < 0.01) and tubulointerstitial (r = -0.71, P < .01) injury. Altogether, these results suggest that specific abnormalities in renal lipid metabolism may be important in the pathogenesis of chronic, progressive renal injury.