Abstract Objective To evaluate the impact of using a novel optical detection system (ODS) as an adjunct to colposcopy. Methods A multicenter internally controlled trial designed to evaluate the performance of an ODS system (LUMA MediSpectra, Lexington, MA) used as an adjunct to colposcopy among women referred for the evaluation of an abnormal cervical cytology result was conducted at 7 colposcopy clinics in the United States and enrolled 227 women. After exclusions, 193 women remained in the analysis. The main study outcomes were incremental increases in true positives (CIN 2,3 and cancer, or CIN 2+) and false positives (women with additional cervical biopsies not found to be CIN 2+). Results Initial colposcopy identified 41 cases of CIN 2+ for a true positive (TP) rate of 21.2%. Adjunctive use of ODS identified an additional 9 cases of CIN 2+ which corresponds to an incremental ODS TP rate of 4.7% (95% CI 2.2% to 8.7%). Adjunctive use of ODS therefore resulted in a 22.0% (95% CI 6.1% to 37.8%) relative gain in the number of women with CIN 2+ compared to colposcopy alone. The false positive (FP) rate for initial colposcopy was 51.8% (100 of 193 women). An additional 35 subjects had an ODS-directed biopsy that was not diagnosed as CIN 2+, yielding an incremental FP rate of 18.1% (95% CI 13.0% to 24.3%). Conclusions Adjunctive use of ODS with colposcopy provides a significant increase in the detection of CIN 2+ in women referred for the evaluation of abnormal cytology results.