Chronic renal failure involves the progressive loss of renal parenchymal cells. For example, Alport syndrome develops from mutated type IV collagen that fosters the digestion of glomerular basement membranes and podocyte loss, followed by progressive glomerulosclerosis, ie Alport nephropathy. Here we show that autosomal recessive Alport nephropathy in collagen 4a3‐deficient mice is associated with increased intrarenal expression of the pro‐apoptotic cytokine tumour necrosis factor‐alpha (TNF‐α) in glomerular cells including podocytes as well as in infiltrating leukocytes. We therefore hypothesized that TNF‐α contributes to Alport glomerulosclerosis by inducing podocyte apoptosis. To address this issue, we treated 4‐week‐old collagen 4a3‐deficient mice with either vehicle or the TNF‐α antagonist etanercept for a period of 5 weeks. Etanercept treatment prolonged mean survival from 68 to 81 days as compared to vehicle‐treated mice. The beneficial effect of etanercept on survival was associated with a significant improvement of the glomerulosclerosis score, proteinuria, and the glomerular filtration rate at 9 weeks of age. Etanercept treatment specifically reduced the numbers of apoptotic podocytes, increased total podocyte counts, and increased the renal mRNA expression of nephrin and podocin without affecting markers of renal inflammation. TNF‐α‐induced podocyte loss is a previously unrecognized pathological mechanism of Alport glomerulosclerosis, and TNF‐α blockade might be a therapeutic option to delay the progression of Alport nephropathy and potentially of other forms of glomerulosclerosis. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.