Background <p>Heart failure with preserved ejection fraction (HFpEF) is a heterogenous clinical syndrome. Individuals living with HFpEF and obesity display a distinct phenotype that places considerable burden on their health-related quality of life. This study explored signs, symptoms, and impacts most relevant to individuals living with HFpEF and obesity. Clinician interviews provided a clinical perspective on the patient experience.</p> Methodology <p>Qualitative interviews were conducted virtually with adults in the US diagnosed with HFpEF and obesity (body mass index ≥ 30.0&#xa0;kg/m2). Clinicians in the US, China, and Germany with ≥ 3 years of experience treating HFpEF were also interviewed. Patient interviews were conducted until conceptual saturation was achieved. Content analysis was conducted using Atlas.ti v9.0 software. A conceptual model (CM) of the lived experience of HFpEF and obesity based on patient and clinician feedback was developed.</p> Results <p>Twenty-two patients and 6 clinicians participated. The CM demonstrated that living with HFpEF impacts many facets of life, with patient and clinician participants reporting impacts on their (or their patients’) physical functioning (e.g., walking), activities of daily living (e.g., household chores) and work. Impacts on emotional well-being (e.g., feeling anxious or worried), social lives, relationships, and sleep were also reported. Shortness of breath and fatigue were spontaneously noted as salient and bothersome symptoms by most patient participants with edema noted by most on probing; this was further corroborated by clinicians who also considered these symptoms as the most bothersome symptoms of HFpEF.</p> Conclusions <p>This study highlighted the substantial burden of living with HFpEF and obesity. The resultant conceptual model highlights the key concepts that should be considered in patient-focused drug development.</p>