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To assess the feasibility of detecting signature volatile organic compounds in the breath of patients with oral squamous cell carcinoma.Prospective cohort pilot study.University hospital.Using gas chromatography and mass spectrometry, emitted volatile organic compounds in the breath of patients before and after curative surgery (n = 10) were compared with those of healthy subjects (n = 4). It was hypothesized that certain volatile organic compounds disappear after surgical therapy. A characteristic signature of these compounds for diseased patients was compiled and validated.Breath analyses revealed 125 volatile organic compounds in patients with oral cancer. A signature of 8 compounds that were characteristic for patients with oral cancer could be detected: 3 from this group presented were absent after surgery.The presented results confirmed the hypothesis of an absence of cancer-associated volatile organic compounds in the breath after therapy. In this pilot study, we proved the feasibility of this test approach. Further studies should be initiated to establish protocols for usage in a clinical setting.