The prevalence of patients on mechanical ventilation who are being supported at home is increasing. Due to these patients’ complex and chronic conditions, the subjective burden on their family caregivers increases after discharge. The aim of this study was to evaluate the effectiveness of a supportive home care program on the caregiver burden of families caring for patients on invasive mechanical ventilation at home. Sixty patients hospitalized in three university-affiliated hospitals in Tehran, Iran between 7/2020 and 8/2021 were randomly assigned to one of two groups: A supportive home care program, and routine hospital education. The supportive home care program included six educational sessions delivered in the hospital before discharge, and home visits and continued education after discharge. Caregiver burden was measured using the Zarit Burden Interview. Results showed that caregiver burden increased significantly ( p ≥ .001) after discharge without the supportive home care program intervention. Follow-up by nurses after discharge is essential to reduce the psychological burden of caring for patients on invasive mechanical ventilation at home.