Optical technologies, such as reflectance and fluorescence spectroscopy, have shown the potential to provide improved point-of-care detection methods for cervical neoplasia that are sensitive, specific, and cost-effective. Our specific goals are to analyze the diagnostic potential of reflectance and fluorescence spectra, alone and in combination, to discriminate normal and precancerous cervical tissue in vivo and to identify which classification features contain significant diagnostic information. Reflectance spectra are measured at four source-detector separations and fluorescence emission spectra are measured at 16 excitation wavelengths, from 324 sites in 161 patients. These 20 spectral features are permuted in all possible combinations of one, two, and three; and classification algorithms are developed to evaluate the diagnostic performance of each combination. Algorithms based on fluorescence spectra alone yield better diagnostic performance than those based on reflectance spectra alone. The combination of fluorescence and reflectance do not significantly improve diagnostic performance compared to fluorescence alone, except in the case of discriminating high-grade precancers from columnar normal tissue. In general, fluorescence emission spectra at 330- to 360-nm and 460- to 470-nm excitation provide the best diagnostic performance for separating all pairs of tissue categories. © 2005 Society of Photo-Optical Instrumentation Engineers.