Background: To evaluate the effectiveness of Microlux/DL with and without toluidine blue in screening of potentially malignant and malignant oral lesions. Materials and Methods: In this diagnostic clinical trial clinical examination was carried out by two teams: 1) two oral medicine consultants, and 2) two general dentists. Participants were randomly and blindly allocated for each examining team. A total of 599 tobacco users were assessed through conventional oral examination (COE); the examination was then repeated using Microlux/DL device and toluidine blue. Biopsy of suspicious lesions was performed. Also clinicians opinions regarding the two tools were obtained. Results: The sensitivity and, specificity and positive predictive value (PVP) of Microlux/DL for visualization of suspicious premalignant lesions considering COE as a gold standard (i.e screening device) were 94.3%, 99.6% and 96.2% respectively, while they were 100%, 32.4% and 17.9% when considering biopsy as a gold standard. Moreover, Microlux/DL enhanced detection of the lesion and uncovered new lesions compared to COE, whereas it did not alter the provisional clinical diagnosis, or alter the biopsy site. On the other hand, adding toluidine blue dye did not improve the effectiveness of the Microlux/DL system. Conclusions: The Microlux/DL seems to be a promising adjunctive screening device.