Breath analysis is highly acceptable to patients and health care professionals, but its implementation in clinical practice remains challenging. Clinical trials and routine practice require a robust system for collection, storage, and processing of large numbers of samples. This work describes a platform based upon the hyphenation of thermal desorption (TD) with proton transfer reaction time-of-flight mass spectrometry (PTR-ToF-MS), coupled by means of an original modification of the TD interface. The performance of TD-PTR-ToF-MS was tested against seven oxygenated volatile organic compounds (VOCs), belonging to three chemical classes (i.e., fatty acids, aldehydes, and phenols), previously identified as possible biomarkers of colorectal and esophago-gastric adenocarcinoma. Limits of detection and quantification were on the order of 0.2-0.9 and 0.3-1.5 parts per billion by volume (ppbV), respectively. Analytical recoveries from TD tubes were 80% or higher, linear response was in the low- to mid-ppbV range ( R2 = 0.98-0.99), and coefficients of variation were within 20% of mean values. The usability of the platform was evaluated in the analysis of a set of breath samples of clinical origin, allowing for a throughput of nearly 100 TD tubes for 24 h of continuous operation. All of these characteristics enhance the implementation of TD-PTR-ToF-MS for large-scale clinical studies.