Multimodal optical imaging, incorporating reflectance and fluorescence modalities, is a promising tool to detect oral premalignant lesions in real‐time.

Images were acquired from 171 sites in 66 patient visits for clinical evaluation of oral lesions.

An automated algorithm was used to classify lesions as high‐ or low‐risk for neoplasia.

Biopsies were acquired at clinically indicated sites and those classified as high‐risk by imaging, at the surgeon's discretion.