Background: Coronavirus Disease 19 (COVID-19)-associated pneumonia is characterized by a broad spectrum of severity. Endothelial injury is a prominent component of the disease, but the relative contribution of vessels of different sizes to this condition has not been extensively investigated. Quantitative computed tomography (CT) represents a potential tool to evaluate pulmonary vascular involvement. Objectives: To investigate the relative contribution of vessels of different sizes in COVID-19-associated pneumonia of different severity using the Computer-Aided Lung Informatics for Pathology Evaluation and Rating (CALIPER) software. Methods: We conducted a single-center retrospective study, including patients admitted to the Pisa University Hospital between March and April 2020 with COVID-19-associated pneumonia. We excluded patients with severe motion artifacts, inadequate CALIPER segmentation, or inconclusive etiologic confirmation. All CT scans were analyzed using CALIPER, which automatically segmented lung parenchyma and vascular-related structures (VRSs). VRS volumes were stratified by vessel cross-sectional area (20 mm²). Results: We analyzed 258 patients. We observed that an increase in the percentages of VRSs with cross-sectional areas up to 20 mm² was associated with the need for lower intensity of care and with better gas exchange. The opposite trend was observed for the percentages of >20 mm². Conclusions: Our data provide novel information on the involvement of blood vessels of different sizes in the gas exchange impairment of COVID-19 patients. CALIPER represents a promising application for the study of vascular structures of the lung.