Aminonucleoside nephrosis progresses over an 18-week period to focal and segmental glomerulosclerosis (FSGS). Whole heparin has been shown to blunt the extent of renal injury in another model of FSGS, renal ablation; however, the precise mechanism of protection has remained uncertain. Since heparin has a variety of physiologic actions unrelated to anticoagulation, we administered three different heparin compounds, each with a distinct profile of biological properties, to groups of rats given a single intravenous dose of puromycin aminonucleoside (PA). In the absence of a prolongation of the activated partial thromboplastin time (aPTT), both whole heparin (WH) and a 7,000- to 11,000-dalton-molecular-weight nonanticoagulant heparin (NAH) ameliorated the functional and histologic abnormalities of chronic aminonucleoside nephrosis as evidenced by significant reductions in 24-hour urine protein excretion while preserving the glomerular filtration rate and blunting the rise in serum creatinine as compared to untreated PA control animals at the conclusion of the study. In addition, the NAH and WH groups exhibited significantly fewer glomeruli with either segmental mesangial proliferative areas or glomerulosclerosis/hyalinosis lesions 18 weeks after PA administration. A fragment of heparin (HF) was ineffective. We conclude that heparin may exert its beneficial effect in chronic aminonucleoside nephrosis through a biologic action, other than anticoagulation, perhaps by inhibition of mesangial cell proliferation.