Enamel demineralization is a recognized risk of full-fixed orthodontic treatment. Current technologies to detect early demineralization (DIAGNOdent and QLF) can be compromised by the oral environment, resulting in false positives. Optical coherence tomography (OCT) and polarized Raman spectroscopy (PRS) can potentially be used to better distinguish sound from demineralized enamel in vitro. Objective: To determine whether calculus, stain, and hypocalcification are confounding factors affecting early caries (demineralization) detection with OCT and PRS. Methods: Extracted human teeth were clinically examined for sound enamel (n=57), early caries (n=13), calculus (n= 20), hypocalcification (n=14), and stain (n=45). OCT and PRS measurements were undertaken, OCT images analyzed, and Raman depolarization ratios (RDRs) calculated (p2/p1). Results: OCT imaging differentiated early caries from sound enamel, calculus, hypocalcification, and stain based on the light back-scattering and characteristic triangular shape of early caries. Average RDRs were consistently larger for demineralized than sound enamel and were statistically significant (p<0.05) between groups, except between sound enamel vs. hypocalcification and early caries vs. stain. Conclusions: OCT and PRS can detect demineralization with high sensitivity and specificity. Calculus and hypocalcification are not confounding factors for these technologies. Stain does not confound OCT, and with improved Raman spectra analysis it will likely not confound PRS. Combining OCT and PRS into one measuring instrument can help decrease false-positive readings and may be valuable in early demineralization detection in clinical orthodontics. A new fibre-optic probe combining OCT and PRS is being developed for pre-clinical testing to accurately detect early demineralization around orthodontic brackets in vivo.