We present a 51-year-old Caucasian woman, with a medical history of systemic lupus erythematosus (SLE) who had dyspnoea at exertion. The SLE was clinically quiescent but serologically active. Echocardiography showed preserved left ventricular (LV) systolic function, pseudonormal mitral inflow pattern (diastolic dysfunction grade III), absence of wall motion abnormalities and elevated E/e' at exercise. An exercise right heart catheterisation was performed, confirming the diagnosis of heart failure with preserved ejection fraction (HFpEF). In the absence of other possible causes, we assumed that HFpEF was mediated by systemic inflammation secondary to SLE. Based on the Paulus' paradigm, that systemic inflammation may lead to diastolic dysfunction, we decided to add belimumab (a biological agent against soluble B-lymphocyte stimulator protein). After 16 weeks of treatment, patient reported an improved condition. Also, cardiopulmonary exercise test and echocardiography results improved, confirming resolution of the underlying LV diastolic dysfunction. This case supports the idea that targeting inflammation has therapeutic potential in a subset of HFpEF-patients.