1. Cyclo-oxygenase (COX)-2 is involved in constitutive production of prostanoids in the kidney and plays a role in the control of renal function and morphology. Renal cortical COX-2 expression and function is increased in experimental models of diabetes (DM). However, pathophysiological roles of this phenomenon in the diabetic kidney have not been fully elucidated. To address this issue, we studied the nephroprotective potential of long-term (16 weeks) COX-2 inhibition in uninephrectomized streptozotocin-diabetic rats (D). 2. Diabetic rats received either a low or high dose of the selective COX-2 inhibitor MF-tricyclic (MF; 1 or 5 mg/kg per day in chow). Another group of D rats received high-dose MF as late intervention starting at 8 weeks of DM (D-MFlate). The effects of treatments were compared with age-matched uninephrectomized diabetic and non-diabetic rats receiving drug-free chow (D-VE and C-VE, respectively). 3. No differences in blood pressure and metabolic control were observed between groups of D rats throughout the study. The D-VE group developed progressive albuminuria and glomerulosclerosis, associated with increased excretion of the thromboxane (TX) A(2) metabolite TxB(2). Treatment with MF attenuated albuminuria in diabetic rats with late intervention, but not in D rats treated with MF from the onset of DM. Moreover, D-MFlate rats demonstrated a significant reduction in the development of glomerulosclerosis. These effects coincided with prevention of diabetes-induced rise in urinary TxB(2) excretion. 4. In conclusion, long-term COX-2 inhibition is associated with modest nephroprotection in uninephrectomized diabetic rats when administered as late intervention. These effects are independent of metabolic control and blood pressure.