BACKGROUND: Heart failure (HF) is a complex, life-threatening condition marked by high morbidity, mortality, reduced functional capacity, poor quality of life, and substantial health care costs. HF with reduced ejection fraction (HFrEF) represents the subgroup of HF with the highest risks of mortality and hospitalization, necessitating the prioritization of care and management models to optimize treatment outcomes in these patients. Currently, data on the effectiveness of telemedicine models in resource-limited settings, such as low- and middle-income countries, are scarce. OBJECTIVE: This study aimed to evaluate the impact of telemedicine on improving prognosis in patients with HFrEF in Vietnam. METHODS: In this prospective cohort study, we recruited patients who received either remote monitoring and management (telemedicine) or standard monitoring and management (usual care) in the outpatient department of the Vietnam National Heart Institute, Bach Mai Hospital, Hanoi, Vietnam. Eligible patients were ≥18 years old, had a diagnosis of HFrEF defined as left ventricular ejection fraction (LVEF) ≤40%, had a history of HF hospitalization within the past 12 months, and presented with clinical symptoms classified as New York Heart Association (NYHA) II or III. The primary composite outcome was defined as the time to the first unplanned HF hospitalization or all-cause mortality. The follow-up period for all outcomes extended to 12 months. RESULTS: In total, 426 patients (298/426, 70% male; 128/426, 30% female) with a mean age of 61.3 (SD 14.6) years and a mean LVEF of 32.1% (SD 6.0%) were included in our study. Of these patients, 121 received telemedicine care, while 305 received usual care. The primary outcome occurred in 23 (23/121, 19%) patients in the telemedicine group and 82 (82/305, 26.9%) patients in the usual care group during the follow-up period, indicating a significant reduction in risk (adjusted hazard ratio [aHR] 0.57, 95% CI 0.35-0.94; P=.03). However, this effect was primarily driven by a significant reduction in unplanned HF hospital admissions (aHR 0.57, 95% CI 0.33-0.98; P=.04) rather than in all-cause mortality (aHR 0.77, 95% CI 0.36-1.63; P=.49). CONCLUSIONS: This study demonstrates that a simplified telemedicine model, even in resource-limited settings such as Vietnam, can effectively facilitate the remote monitoring and management of patients with HFrEF, resulting in significant reductions in HF-related hospitalizations and all-cause mortality. TRIAL REGISTRATION: National Agency for Science and Technology Information (NASATI), Vietnam CT07/01-2022-3; https://nsti.vista.gov.vn/projects/dth/xay-dung-mo-hinh-theo-doi-va-tu-van-suc-khoe-tim-mach-tu-xa-tai-thanh-pho-ha-noi-109276.html.