Background: Patients with heart failure with preserved ejection fraction (HFpEF) have poor health-related quality of life (HR-QoL). However, the relationship between HR-QoL measures and the alterations of cardiac structure and function that are present in patients with HFpEF remains unknown. Aims: To study the associations between HR-QoL and echocardiographic parameters in HFpEF. Methods: Regression modelling in patients from TOPCAT-Americas who had both HR-QoL questionnaires and a baseline echocardiogram. Results: A total of 631 patients (36% of the TOPCAT-Americas population) had both echocardiographic and HR-QoL at baseline. KCCQ-23 Overall Summary Score (OSS; 0-100 points) was negatively (higher echocardiographic values-poorer/lower HR-QoL scores) associated with left ventricular end-diastolic diameter (LVEDD: β = -3.56 [-7.00 to -0.13] points-per-1 cm, P = 0.042), interventricular septum thickness (β = -1.31 [-2.19 to -0.42] points-per-1 mm, P = 0.004), posterior wall thickness (β = -1.57 [-2.52 to -0.63] points-per-1 mm, P = 0.001 and left atrial width (β = -3.27 [-6.39 to -0.15], P = 0.040) points-per-1 cm, and positively (higher echocardiographic values-better/higher HR-QoL scores) associated with left ventricular end-diastolic volume index (LVEDVi: β = 0.23 [0.09 to 0.37] points-per-1 ml/m2, P = 0.002) and left ventricular end-systolic volume index (LVESVi: β = 0.41 [0.18 to 0.63] points-per-1 ml/m2, P < 0.001). Body mass index (BMI: β = -0.74 [-1.02 to -0.47] points-per-1Kg/m2, P < 0.001), diabetes (β = -6.01 [-10.05 to -1.97], P = 0.004), and asthma (β = -6.78 [-13.52 to -0.04], P = 0.049) were negatively associated with OSS. A similar pattern of associations was observed for KCCQ-23 Clinical Summary Score, EQ5D-VAS and NYHA class. Conclusion: In patients with HFpEF, HR-QoL measures were associated with cardiac structure and function alterations. Extra-cardiac factors were also associated with HR-QoL, which may influence HR-QoL results when testing cardiovascular drugs.