Treatment with conventional heparin is effective in experimental mesangioproliferative glomerulonephritis. However, the long-term effects and safety of this therapy, in particular in the presence of mesangiolysis, have not been assessed. In addition, this therapy has been hampered by bleeding complications. In the present study, therefore, we investigated the long-term effects of a short course of non-anticoagulant (NA) heparin treatment in the anti-Thy 1.1 mesangioproliferative glomerulonephritis, in which early immune-mediated mesangiolysis subsequently leads to mesangial hyperproliferation. Rats received continuous ip NA-heparin or vehicle during the active mesangioproliferative phase (Days 2 to 9; early treatment) or during the early resolution phase (Days 10 to 17; late treatment). Whereas NA-heparin in the early treatment group did not affect the glomerular macrophage, lymphocyte, or platelet influx, it did lead to significantly decreased glomerular cellularity, mesangial cell proliferation, alpha-smooth muscle actin, desmin expression (ie, markers of activated mesangial cells), and matrix accumulation as well as to persistent mesangiolytic lesions including microaneurysms. Despite this latter finding, at Day 120, NA-heparin-treated rats of the early treatment group showed significantly better renal function and less proteinuria and glomerulosclerosis than vehicle-infused rats. In contrast, late therapy with NA-heparin neither accelerated resolution of the nephritis or otherwise affected the course of the disease. We conclude that transient NA-heparin therapy is effective in mesangioproliferative glomerulonephritis, both acutely and long term, when it is initiated during the active phase of the disease. Also, NA-heparin therapy is safe even in glomerular diseases accompanied by mesangiolysis.