Thin basement membrane disease (TBMD) is a condition originally defined as diffuse thinning of the glomerular basement membrane (GBM) associated with hematuria in all patients. Although proteinuria has been described in up to 60% of patients with TBMD, it is almost always mild, with a 24-hour excretion mostly of less than 500 mg. We describe eight patients (four men and four women between 32 and 66 years of age) with TBMD who presented with heavy proteinuria or nephrotic syndrome. Among the seven cases with family history, hematuria was noted in five. All patients had a long history of microscopic hematuria, with episodic gross hematuria in two. Renal biopsies showed diffuse thinning of the GBM in each patient (mean between 185.3 x 29.8 nm and 232.6 x 34.5 nm versus control between 325 x 35 nm and 350 x 15 nm). Three cases showed thinning of GBM only (group I); the remaining five cases showed thinning of GBM associated with focal segmental glomerulosclerosis. All three patients of group I presented with nephrotic syndrome and normal renal function. Treatment with steroids resulted in remission of nephrotic syndrome in two, whereas nephrotic syndrome persisted in the untreated patient. Among the five patients in group II, nephrotic syndrome and normal renal function at presentation were noted in two, whereas the other three had heavy proteinuria (2.2, 2. 5, and 2.6 g/d, respectively) associated with mildly decreased renal function (serum creatinine 1.8, 1.3, and 1.5 mg/dL, respectively). At last follow-up, although the renal function was stable in all five, only the three who received steroid treatment had remission or marked improvement of proteinuria. Hematuria, however, persisted in all eight patients of both groups. Whether specific gene mutations are translated into structural changes responsible for both excessive GBM thinning and increased transcapillary permeability remains to be elucidated. Alternatively, the heavy proteinuria/nephrotic syndrome may not be related to TBMD, but rather is the manifestation of associated glomerular diseases. Follow-up, including a response to steroids, supports the latter hypothesis.