Obesity is common in heart failure with preserved ejection fraction (HFpEF). Whether obesity modifies the response to spironolactone in patients with HFpEF remains unclear. We aimed to investigate the effect of obesity, defined by body mass index (BMI) and waist circumference (WC), on response to spironolactone in patients with HFpEF enrolled in TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial. This was a post-hoc, exploratory analysis of the Americas cohort of TOPCAT. BMI≥30 kg/m2 was used to define the obese group and WC≥102cm in men and ≥88cm in women were defined as high WC (HWC). In separate analyses, BMI and WC were treated as continuous variables. The effect of spironolactone vs. placebo on outcomes was calculated by BMI and WC using Cox proportional hazard models. Obese patients were younger and had more comorbidities. In multivariate analysis, spironolactone use was associated with a significant reduction in the primary endpoint, compared to placebo in obese [hazard ratio (HR=0.618, 95% CI 0.460-0.831, p=0.001), but not in non-obese subjects (HR=0.946, 95% CI 0.623-1.437, p=0.796; p for interaction=0.056). There was a linear association between continuous BMI and the effect of spironolactone, with the effect becoming significant at 33kg/m2. Similar results were obtained for the WC-based analysis. In conclusion, use of spironolactone in obese patients with HFpEF was associated with a decreased risk of the primary endpoint, cardiovascular death and HF hospitalizations, compared to placebo. Further prospective randomized studies in obese subjects are required.