Bone marrow (BM) transplantation has been shown to provide beneficial effects in injured organs, including heart, liver, and kidney. We explored the therapeutic potential of BM transplantation (BMT) in Wilms' tumor suppressor 1 (Wt1) heterozygous mice, which represent a model of mesangial sclerosis. After transplantation of wild-type BM, there is statistically significantly lower urinary albumin and increased survival in Wt1+/− recipients. Control BMT using Wt1+/− donors showed no significant beneficial effects. The long-term beneficial effect of BMT was dependent on the dose of irradiation applied to the recipients before BMT. At a lethal dose of 1,000 cGy, the decrease in albuminuria and prolongation of lifespan in Wt1+/− mice were transient, with maximal amelioration at 12 weeks and resumption of albuminuria by 24 weeks after BMT. This was, at least in part, due to irradiation and not Wt1 heterozygosity because wild-type recipients also developed albuminuria within 24 weeks of BMT with 1,000 cGy. In contrast, Wt1+/− mice transplanted after 400 cGy showed long-term improvement in albuminuria and lifespan. Approximately 0.4% of podocytes were marrow derived, a level that is unlikely to be responsible for the therapeutic effects. In addition, donor BM cells formed rings surrounding the glomeruli, and approximately one third of the cells in these rings were macrophages. In conclusion, transplantation of wild-type BM attenuates progression of mesangial sclerosis in the Wt1+/− model of renal disease, and the mechanism by which this occurs may involve engraftment of BM-derived cells in the renal parenchyma.