<b><i>Introduction:</i></b> The effect of mineralocorticoid receptor antagonists (MRAs) on chronic kidney disease (CKD) progression in patients with heart failure (HF) and with or without preexisting CKD has not been adequately studied. <b><i>Methods:</i></b> We conducted a retrospective cohort study including consecutive adult patients followed at the HF clinic of a tertiary care center who had already been on an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB). Exposure to MRAs was assessed at 6 months from registration. Patients who were never exposed to an MRA were the control group. <b><i>Results:</i></b> A total of 314 patients who were prescribed an MRA were compared to 1,116 patients who never received an MRA. Among them, 121 and 408 patients, respectively, had CKD (estimated glomerular filtration rate &#x3c;60 mL/min/1.73 m²). MRAs had to be discontinued in 36/121 patients with CKD (29.8%) and 57/165 patients without CKD (34.5%) (<i>p</i> = 0.39). MRA treatment was associated with a higher risk for persistent creatinine doubling among patients without CKD (hazard ratio 4.07, 95% confidence interval 1.41–11.73). A numerically lower risk was identified among CKD patients (hazard ratio 0.33, 95% confidence interval 0.04–2.78) (<i>p</i> for interaction = 0.009). The primary safety outcome, a composite of any doubling of serum creatinine or any episode of serious hyperkalemia (K⁺ &#x3e;6 mmol/L), occurred more commonly in MRA users compared with nonusers in the subgroup of patients without CKD, but not in CKD patients (<i>p</i> for interaction = 0.02). <b><i>Conclusion:</i></b> MRA treatment in addition to an ACEI or an ARB could be safely prescribed in HF patients with CKD as it is not associated with persistent renal function decline, acute kidney injury, or serious hyperkalemia, compared with ACEI/ARB monotherapy.