Estrogens have a protective effect on kidney fibrosis in several animal models. Here, we tested the effect of raloxifene, an estrogen receptor modulator, on the change in serum creatinine or estimated glomerular filtration rate (eGFR) and incident kidney-related adverse events. We performed a post-hoc analysis of the multiple outcomes of raloxifene evaluation trial, a double-masked, placebo-controlled randomized clinical trial encompassing 7705 post-menopausal women (aged 31–80 years) with osteoporosis. Participants were randomized to either of two doses of raloxifene, 60 or 120 mg/day, or placebo. Serum creatinine was measured at a central laboratory at baseline and annually. Adverse events were assessed every 6 months and uniformly categorized. Compared with those in the placebo group, participants on raloxifene had a slower yearly rate of increase in creatinine (significant at the low dose) and a significantly slower yearly rate of decrease in eGFR for both doses over 3 years of follow-up. Raloxifene was associated with significantly fewer kidney-related adverse events compared with placebo. Thus, treatment with raloxifene was safe and renoprotective. Clinical trials of raloxifene in post-menopausal women with kidney disease designed to look at kidney outcomes are needed to confirm these findings.