We prospectively evaluated a platelet-inhibitor regimen of dipyridamole and aspirin in 28 patients with insulin-dependent diabetes mellitus and well-established nephropathy. After a mean treatment period of 4.3 years, iothalamate clearance (Ciot) was reasonably well maintained and urinary protein excretion was reduced in 7 patients (25%), whereas 21 (75%) had progressive nephropathy. Analysis of outcome revealed that all 7 patients with stable nephropathy and 9 of the 21 with progressive disease had baseline Ciot values that exceeded 50 ml/min per 1.73 m2. Shortened platelet survival improved after 3 months of treatment, and the distribution between patients who had stable and those who had progressive disease was approximately equal. Mean changes in fasting plasma glucose level, glycosylated hemoglobin, and blood pressure did not differ between these two groups. In a short-term protocol, urinary protein and thromboxane B2 significantly declined, whereas variable urinary levels of prostaglandin E2, 6-ketoprostaglandin F1 alpha, and Ciot did not change after 3 months of treatment with dipyridamole and aspirin. These findings suggest that treatment with dipyridamole and aspirin may stabilize renal function by reducing platelet hypersensitivity and production of thromboxanes by platelet or renal tissue (or both). In turn, constrictor activity in the glomerular vessels, mesangial contractility, and glomerular membrane permeability are decreased. These data also add evidence in support of a role for thromboxane A2 in the pathogenesis of experimental and human glomerular disease.