The relations among renal function, proteinuria, and glomerular lesions were studied in 54 patients with reflux nephropathy. The clinical course to end-stage renal disease was not appreciably altered by late surgical correction of the reflux, occurrence of urinary tract infection, or hypertension. All patients with progressive renal disease had significant proteinuria. Mesangial glomerular lesions can occur in the absence of proteinuria detectable by routine urinalysis, whereas lesions similar to those seen in idiopathic focal sclerosing glomerulopathy were present in the renal biopsies from proteinuric patients. Deposition of immunoproteins was limited to glomeruli undergoing sclerosis. Similarly, electron-dense deposits were confined to areas of mesangial alterations. Our results suggest that mesangial alterations occur early in the course of reflux nephropathy and may lead to the development of focal sclerosis. At later stages, counterproductive mechanisms of adaptation to the loss of viable nephrons might result in an acceleration of the clinical course to renal failure.