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Introduction: The incidence of oral squamous cell carcinoma (OSCC) shows a constant increase, while the long-term outcome remains poor over the last decades. Radical oxygen and nitrogen species (RONS) - initially released by carcinogens, such as alcohol and tobacco, and later maintained by the tumor microenvironment - appear to be strongly associated to chronic inflammation, tumor induction, progression, and metastatic spread. The aim of this study was to evaluate the role of oxidative and nitrosative stress in primary OSCC compared to healthy tissue specimens and to identify their impact on tumor carcinogenesis., Materials and Methods: In this basic research study, tissue samples of 30 patients with primary OSCC were evaluated for the expression of pAKT, pERK, 3-NT, NOS1, NOS3, MAPK1, and IP-8 by immunohistochemistry and RT-PCR and compared to those of a healthy control group (n = 30)., Results: The results showed a significantly increased expression of pAKT (p < 0.001), pERK (p = 0.01), 3-NT (p = 0.039), NOS1 (p = 0.025), NOS3 (p = 0.046), and MAPK1 (p = 0.032) in OSCC tissue samples compared to healthy controls., Conclusion: The results of this study prove the tested stable degradation products to be suitable for the detection of RONS in OSCC. Moreover, the significantly increased expression underlines the role of RONS in carcinogenesis of OSCC, suggests specific mechanisms of detection, and anticipates supplementary research., (© 2020 The Author(s) Published by S. Karger AG, Basel.)