BACKGROUND: The elastic scattering spectroscopy (ESS) device (DermaSensor Inc., Miami, FL) is a noninvasive, painless, adjunctive tool for skin cancer detection. OBJECTIVES: To investigate the performance of the ESS device in the detection of melanoma. METHODS: A prospective, investigator-blinded, multicenter study was conducted at 8 United States (US) and 2 Australian sites. All eligible skin lesions were clinically concerning for melanoma, examined with the ESS device, subsequently biopsied according to dermatologists standard of care, and evaluated with histopathology. A total of 311 participants with 440 lesions were enrolled, including 44 melanomas (63.6% in situ and 36.4% invasive) and 44 severely dysplastic nevi. RESULTS: The observed sensitivity of the ESS device for melanoma detection was 95.5% (95% CI, 84.5% to 98.8%, 42 of 44 melanomas), and the observed specificity was 32.5% (95% CI, 27.2% to 38.3%). The positive and negative predictive values were 16.0% and 98.1%, respectively. LIMITATIONS: The device was tested in a high-risk population with lesions selected for biopsy based on clinical and dermoscopic assessments of board-certified dermatologists. Most enrolled lesions were pigmented. CONCLUSION: The ESS devices high sensitivity and NPV for the detection of melanoma suggest the device may be a useful adjunctive, point-of-care tool for melanoma detection.