We report the results of an oral cavity pilot clinical trial to detect early precancer and cancer using a fiber optic probe with obliquely oriented collection fibers that preferentially probe local tissue morphology and heterogeneity using oblique polarized reflectance spectroscopy (OPRS). We extract epithelial cell nuclear sizes and 10 spectral features. These features are analyzed independently and in combination to assess the best metrics for separation of diagnostic classes. Without stratifying the data according to anatomical location or level of keratinization, OPRS is found to be sensitive to four diagnostic categories: normal, benign, mild dysplasia, high-grade dysplasia, and carcinoma. Using linear discriminant analysis, separation of normal from high-grade dysplasia and carcinoma yield a sensitivity and specificity of 90 and 86%, respectively. Discrimination of morphologically similar lesions such as normal from mild dysplasia is achieved with a sensitivity of 75% and specificity of 73%. Separation of visually indistinguishable benign lesions from high-grade dysplasia and carcinoma is achieved with good sensitivity (100%) and specificity (85%), while separation of benign from mild dysplasia gives a sensitivity of 92% and a specificity of 69%. These promising results suggest that OPRS has the potential to aid screening and diagnosis of oral precancer and cancer.