Abstract Objective. To assess whether the use of a novel optical detection system (ODS) as an adjunct to colposcopy increases the detection of biopsy-confirmed CIN 2,3. Methods. This is a multicenter two-arm randomized trial comparing colposcopy alone with colposcopy plus a pre-commercial ODS system that utilizes fluorescence, white light tissue reflectance, and cervical video imaging. Patients were recruited from 13 colposcopy clinics in a variety of practice settings. 2299 women referred for the evaluation of an abnormal cervical cytology were randomized with stratification by cytology; subsequently 113 women were excluded for a variety of reasons. The main study outcomes were differences in true-positive rates (CIN 2,3 and cancer identified) and false-positive rates between the study arms. Results. The true-positive (TP) rates were 14.4% vs. 11.4% ( p = 0.035, one-sided) for the combined colposcopy and ODS arm compared to colposcopy-only arm, respectively, in women with either an atypical squamous cell (ASC) or low-grade squamous intraepithelial lesion (LSIL) cytology result. TP rates were similar between the two arms among women referred for the evaluation of HSIL. The 26.5% gain in true-positives observed with the use of ODS and colposcopy among women referred for an ASC or LSIL cytology was achieved with only a fractional increase in number of biopsies obtained per patient (0.30) and a modest increase in false-positive rate (4%). In the combined colposcopy and ODS arm among women with ASC or LSIL, the PPV of biopsies indicated by ODS was 15.0% and the PPV of biopsies indicated by colposcopy was 15.2%. Joint hypothesis testing indicates that ODS and colposcopy provides benefit compared to colposcopy alone among women with ASC or LSIL. Conclusions. Combining ODS with colposcopy provides a clinically meaningful increase in the detection of CIN 2,3 in women referred for the evaluation of mildly abnormal cytology results.