Studies in experimental animals and younger women suggest a protective role for estrogen; however, clinical trials may not substantiate this effect in older females. Therefore, the current study assessed the outcome of ovariectomy in older mRen2.Lewis rats subjected to a high salt diet for 4 weeks. Intact or ovariectomized (OVX, 15 weeks of age) mRen2.Lewis rats were aged to 60 weeks and then placed on a high salt (HS, 8% sodium chloride) diet for 4 weeks. The systolic blood pressures were similar between groups [OVX: 169 ± 6 mmHg vs. Intact: 182 ± 7 mmHg, p=0.22] following the 4 week diet; however, the proteinuria [OVX: 0.8 ± 0.2 mg/mg creatinine vs. Intact: 11.5 ± 2.6 mg/mg creatinine, p0.002, n=6], renal interstitial fibrosis, glomerular sclerosis and tubular casts were lower in the OVX group versus Intact rats. KIM-1 mRNA, a marker of tubular damage, was 53% lower in the OVX HS group. Independent from blood pressure, the OVX high salt rats exhibited significantly lower cardiac (24%) and renal (32%) hypertrophy as well as lower C-reactive protein (28%). Circulating insulin-like growth factor-1 (IGF-1) levels were not different between the Intact and OVX groups; however renal cortical IGF-1 mRNA and protein were attenuated in the OVX rats [p0.05, n=6]. We conclude that ovariectomy in the older female mRen2.Lewis rat conveys protection against the salt-dependent increase in renal injury.