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As early detection is crucial for improvement of cancer prognosis, we searched for biomarkers in plasma from individuals who later developed squamous cell carcinoma of the oral tongue (SCCOT) as well as in patients with an already established SCCOT. Levels of 261 proteins related to inflammation and/or tumor processes were measured using the proximity extension assay (PEA) in 179 plasma samples (42 collected before diagnosis of SCCOT with 81 matched controls; 28 collected at diagnosis of SCCOT with 28 matched controls). Statistical modeling tools principal component analysis (PCA) and orthogonal partial least square - discriminant analysis (OPLS-DA) were applied to provide insights into separations between groups. PCA models failed to achieve group separation of SCCOT patients from controls based on protein levels in samples taken prior to diagnosis or at the time of diagnosis. For pre-diagnostic samples and their controls, no significant OPLS-DA model was identified. Potentials for separating pre-diagnostic samples collected up to five years before diagnosis (n = 15) from matched controls (n = 28) were seen in four proteins. For diagnostic samples and controls, the OPLS-DA model indicated that 21 proteins were important for group separation. TNF receptor associated factor 2 (TRAF2), decreased in pre-diagnostic plasma (< 5 years) but increased at diagnosis, was the only protein showing altered levels before and at diagnosis of SCCOT (p-value < 0.05). Taken together, changes in plasma protein profiles at diagnosis were evident, but not reliably detectable in pre-diagnostic samples taken before clinical signs of tumor development. Variation in protein levels during cancer development poses a challenge for the identification of biomarkers that could predict SCCOT development.