Optical spectroscopy devices are being developed and tested for the screening and diagnosis of cancer and precancer in multiple organ sites. The studies reported here used a prototype of a device that uses white light, green-amber light at 545 nm, and violet light at 405 nm. Given that oral neoplasia is rare, the need for a device that increases the sensitivity of comprehensive white light oral screening is evident. Such a device, in the hands of dentists, family practitioners, otorhinolaryngologists, general surgeons, obstetrician gynecologists, and internists, could greatly increase the number of patients who have lesions detected in the precancerous phase.The objective of this study was to present a case series of oral precancers and cancers that have been photographed during larger ongoing clinical trials.Over 300 patients were measured at 2 clinical sites that are comprehensive cancer centers and a faculty practice associated with a major dental school. Each site is conducting independent research on the sensitivity and specificity of several optical technologies for the diagnosis of oral neoplasia. The cases presented in this case series were taken from the larger database of images from the clinical trials using the aforementioned device. Optical spectroscopy was performed and biopsies obtained from all sites measured, representing abnormal and normal areas on comprehensive white light examination and after use of the fluorescence and reflectance spectroscopy device. The gold standard of test accuracy was the histologic report of biopsies read by the study histopathologists at each of the 3 study sites.Comprehensive white light examination showed some lesions; however, the addition of a fluorescence image and a selected reflectance wavelength was helpful in identifying other characteristics of the lesions. The addition of the violet light-induced fluorescence excited at 405 nm provided an additional view of both the stromal neovasculature of the lesions and the stromal changes associated with lesion growth that were biologically indicative of stromal breakdown. The addition of 545 nm green-amber light reflectance increased the view of the keratinized image and allowed the abnormal surface vasculature to be more prominent.Optical spectroscopy is a promising technology for the diagnosis of oral neoplasia. The conclusion of several ongoing clinical trials and an eventual randomized Phase III clinical trial will provide definitive findings that sensitivity is or is not increased over comprehensive white light examination.