Optical spectroscopy can provide useful diagnostic information about the morphological and biochemical changes related to the progression of precancer in epithelial tissue. As precancerous lesions develop, the optical properties of both the superficial epithelium and underlying stroma are altered; measuring spectral data as a function of depth has the potential to improve diagnostic performance. We describe a clinical spectroscopy system with a depth-sensitive, ball lens coupled fiber-optic probe for noninvasive in vivo measurement of oral autofluorescence and diffuse reflectance spectra. We report results of spectroscopic measurements from oral sites in normal volunteers and in patients with neoplastic lesions of the oral mucosa; results indicate that the addition of depth selectivity can enhance the detection of optical changes associated with precancer.