Background: The renin-angiotensin-aldosterone system participates importantly in the progression of hypertensive renal disease. Angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists have been demonstrated to afford renoprotection in L-NAME-exacerbated nephrosclerosis in SHR rats. This study was designed to examine the effects of the aldosterone antagonist eplerenone on systemic and renal hemodynamics, glomerular dynamics, renal function and histopathology in L-NAME/SHR, and determine whether aldosterone antagonism would enhance the effectiveness of ACE inhibition. Methods: Six groups of 20-week-old SHR were studied using renal micropuncture and histopathological techniques after 3 weeks of treatment: SHR control (tapwater, n = 10); SHR + eplerenone (101 ± 8.3 mg/kg/day, n = 10); SHR + L-NAME (5.0 ± 0.12 mg/kg/day, n = 9); SHR + L-NAME + eplerenone (n = 8); SHR + L-NAME + lisinopril (3 mg/kg/day, n = 9), and SHR + L-NAME + eplerenone + lisinopril (n = 9). Results: L-NAME-treated SHR developed massive proteinuria, severe hypertensive nephrosclerosis, and tubulointerstitial damage. Eplerenone significantly reduced proteinuria (127.4 ± 26.5 vs. 51.9 ± 16.7 mg/24 h, p < 0.01), improved glomerular and arteriolar injuries (65 ± 9 vs. 29 ± 9 score/100 glomeruli, p < 0.01; 116 ± 18 vs. 41 ± 13 score/100 arterioles, p < 0.01, respectively), and decreased tubulointerstitial damage index (1.43 ± 0.07 vs. 0.39 ± 0.07, p < 0.01) without altering mean arterial pressure or glomerular dynamics. Combined therapy of eplerenone with lisinopril produced no further benefits than lisinopril alone. Conclusion: The aldosterone antagonist eplerenone significantly ameliorated proteinuria and nephrosclerosis in the L-NAME/SHR model, independent of hemodynamic effects.