Introduction: Albumin is known to play an important role for transportation of various proteins, peptides and low molecular weight molecules produced by tumor cells. The novel technique of spin labelling followed by electron spin resonance spectroscopy (ESR) is a tool to evaluate the structural and functional changes that can occur to albumin following the binding of various ligands. A difference of albumin functionality between cancer patients and healthy persons has been described in other tumor entities. Therefore, the present study investigated the value of ESR analysis for albumin-bound molecules as a possible biomarker in oral squamous cell carcinoma (OSCC). Material and Method: ESR was tested blinded to the clinical data. Peripheral blood was isolated from 32 patients with histological verified OSCC (m=18, w=14; T1 n=11, T2 n=10, T3 n=6, T4 n=5; N0 n=24, N1 n=6) and tested against 30 healthy volunteers (age and gender matched). A discriminant variable (DR) was calculated. Obtained data were associated with pathological and clinical data. Results: The analysis revealed a diagnostic sensitivity in detection of OSCC of 72% (23/32 patients with OSCC) and a specificity of 80% (24/30 healthy volunteers). A sub-group analysis with patients without leucocyte elevation (52 patients (84%; OSCC-group n=23, healthy volunteers n=29) was conducted. Here, sensitivity added up to 87% (20/23), specificity to 83% (24/29). In both groups, DR was significant different (p 0.001) between OSCC- and volunteer group. ESR measurement "detected" all T4- as well as all N-1 stadiums. Discussion: High sensitivity and specificity implies a promising approach towards detection of OSCC by peripheral blood analysis. Nevertheless, inflammation seems to be a major confounder. As OSCC is often accompanied with inflammation, the method may be not appropriate in these cases. Prospective studies with higher patient numbers and an optional combination with other biomarkers are needed to confirm the value of ESR in OSCC diagnosis. Keywords: oral cancer, diagnosis, electron spin resonance, albumin