Oral cancers, are one of the major cancers among South Asian populations, particularly men. The low 5-year disease-free survival rate of this is attributed to late detection. Several Raman spectroscopy (RS) studies both non-invasive (in vivo) and less invasive (exfoliated cells, serum) have successfully stratified healthy, precancer, cancer, cancer-field-effects, potential recurrences. In view of attributes of serum, viz., transportability for centralized analysis, better patient compliances, in the present study, we have further examined efficacy of serum RS in delineating oral premalignant disorders (OPMD) - often known precede frank tumors- such as oral submucous fibrosis (OSMF-3), leukoplakia (LP-3), lichen planus (L-4) and habitues without lesions (HWL-10), along with healthy (C-8) ,cancer (Ca-10) subjects and Unknown (T- 8).Raman spectra acquired using Witech Raman spectrometer were analysed by principal component analysis (PCA) and PCA-based linear discriminant analysis. Data analysed in two approaches i.e .individual OPMD groups along with control and tumors; pooled OPMD subjects, controls and tumor subjects. Raman spectral features suggest variation among groups in amino acids, lipids, beta-carotene, and DNA content, Multivariate analysis, in both approaches, revealed clear classification of control and tumor groups but OPMD spectra misclassified with cancers/HWLs. Consequent examination of medical records show few of OPMD subjects carried tumors as well. Though, study shows clinical utility of serum RS as a minimally invasive, rapid and objective approach to obtain a reliable screening/diagnostic modality for oral cancers, in view of high misclassifications among OPMD spectra, further studies with a higher sample size is warranted.