Background Therapy with evidence-based heart failure (HF) medications has been shown to be associated with lower risk of 30-day all-cause readmission in patients with HF and reduced ejection fraction (HFrEF). Methods We examined the association of aldosterone antagonist use with 30-day all-cause readmission in this population. Of the 2443 Medicare beneficiaries with HF and left ventricular EF ≤ 35% discharged home from 106 Alabama hospitals during 1998–2001, 2060 were eligible for spironolactone therapy (serum creatinine ≤ 2.5 for men and ≤ 2 mg/dl for women, and serum potassium < 5 mEq/L). After excluding 186 patients already receiving spironolactone on admission, the inception cohort consisted of 1874 patients eligible for a new discharge prescription for spironolactone, of which 329 received one. Using propensity scores for initiation of spironolactone therapy, we assembled a matched cohort of 324 pairs of patients receiving and not receiving spironolactone balanced on 34 baseline characteristics (mean age 72 years, 42% women, 33% African American). Results Thirty-day all-cause readmission occurred in 17% and 19% of matched patients receiving and not receiving spironolactone, respectively (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.64–1.32; p = 0.650). Spironolactone had no association with 30-day all-cause mortality (HR, 0.84; 95% CI, 0.38–1.88; p = 0.678) or HF readmission (HR, 0.74; 95% CI, 0.41 1.31; p = 0.301). These associations remained unchanged during 12 months of post-discharge follow-up. Conclusion A discharge prescription for spironolactone had no association with 30-day all-cause readmission among older, hospitalized Medicare beneficiaries with HFrEF eligible for spironolactone therapy.