Background: Given the promising effects of inspiratory muscle training (IMT), determining the most appropriate IMT protocol will optimize the training benefits. Objectives: The objective of this study was to determine the effects of high intensity interval-based inspiratory muscle training (H-IMT) on cardiovascular, pulmonary, physical, and psychosocial functions in patients with heart failure and reduced ejection fraction (HFrEF). Methods: Thirty-four patients with HFrEF were randomly assigned to the H-IMT or control group for 3 days/week, 8 weeks training period. The H-IMT group performed IMT at least 70% of the maximal inspiratory pressure, whereas the control group performed unloaded IMT. Each session occurred 7 sets with a total of 21 min consisting of 2-min training and 1-min interval. Heart rate variability (HRV), arterial stiffness, respiratory muscle strength and endurance, diaphragm thickness, quadriceps strength, functional capacity, frailty, dyspnea, fatigue, disease-specific health-related quality of life (HRQoL), and generic HRQoL were evaluated at baseline and after 8 weeks training period by blinded assessors. Results: Statistically significant between-group differences were observed in the time domain parameters of HRV, arterial stiffness, inspiratory and quadriceps muscle strength, respiratory muscle endurance, diaphragm thickness, functional capacity, frailty, dyspnea, fatigue, and disease-specific HRQoL in favor of the H-IMT group (p<0.05). Conclusions: H-IMT is an effective protocol for improving cardiac autonomic function, arterial stiffness, inspiratory and quadriceps muscle strength, respiratory muscle endurance, diaphragm thickness, functional capacity, frailty, dyspnea, fatigue, and disease-specific quality of life in patients with HFrEF. Clinical trial registration: NCT04839211