Background: Mechanisms and causes of death in older patients with SARS-CoV-2 infection are still poorly understood. Methods: We conducted in a retrospective monocentric study, a clinical chart review and post-mortem examination of patients aged 75 years and older hospitalized in acute care and positive for SARS-CoV-2. Full body autopsy and correlation with clinical findings and suspected causes of death were done. Results: Autopsies were performed in 12 patients (median age 85 years; median of 4 comorbidities, mainly hypertension and cardiovascular disease). All cases showed exudative or proliferative phases of alveolar damage and/or a pattern of organizing pneumonia. Causes of death were concordant in 6 cases (50%), and undetected diagnoses were found in 6. Five patients died from hypoxemic respiratory failure due to coronavirus disease 2019 (COVID-19), five had another associated diagnosis and two died from alternative causes. Deaths that occurred in the second week were related to SARS-CoV-2 pneumonia whereas those occurring earlier were related mainly to heart failure and those occurring later to complications. Conclusions: Although COVID-19 hypoxemic respiratory failure was the most common cause of death, post-mortem pathological examination revealed that acute decompensation from chronic comorbidities during the first week of COVID-19 and complications in the third week contributed to mortality.