Heart failure (HF) is often associated with the deterioration of the protein quality control (PQC) system and the accumulation of protein aggregates. Evidence from tissue biopsies showed that exercise restores PQC system in HF; however, little is known about its effects on plasma proteostasis. Our study aimed to determine the effects of exercise training on the load and composition of plasma SDS-resistant protein aggregates (SRA) in patients with HF with reduced ejection fraction (HFrEF). To accomplish this goal, the load and content of circulating SRA were assessed using D2D SDS-PAGE and mass spectrometry. The exercise program decreased the plasma SRA load in patients with HFrEF. SRA were composed of 31 proteins, with the extracellular chaperones α-2-macroglobulin and haptoglobin as the most abundant ones. 5 patients with HFrEF were enrolled in a 12-week combined (aerobic plus resistance) exercise program with 2 training sessions per week, for a total of 24 sessions. The inclusion criteria included patients aged ≥ 18 years with a diagnosis of HFrEF according to the criteria of the European Society of Cardiology, clinical stability, optimal medical treatment for ≥6 weeks, and patients able to follow the exercise prescription. Exclusion criteria: patients who have undertaken cardiac rehabilitation within the past 12 months; implantable cardioverter-defibrillator (ICD), cardiac resynchronization therapy (CRT), or combined CRT/ICD device implanted in the last 6 weeks; myocardial infarction in the last 3 months; ischaemia signs during cardiopulmonary exercise testing; symptomatic and/or exercise-induced cardiac arrhythmia or conduction disturbances; currently pregnant or intend to become pregnant in the next year; inability to exercise or conditions that may interfere with exercise intervention; expectation of receiving a cardiac transplant in the next 6 months; participation in another clinical trial; patients who are unable to understand the study information or complete the questionnaires.