n recent decades, the dermatoscope has been thought to be an essential tool for skin cancer diagnosis, and it is currently referred as the "dermatologist's stethoscope." 1-3 However, in some cases the diagnosis of malignant abnormalities is still challenging in a subset of difficult-to-diagnose melanomas (MMs) and nonmelanoma skin cancers. To narrow this gray zone, reflectance confocal microscopy (RCM), a second-level in vivo imaging technique, has proven to be a useful tool in saving unnecessary excisions of benign lesions that can look dermoscopically suspicious for skin cancer while catching MMs that are dermoscopically inconspicious. 4-8 Reflectance confocal microscopy provides a horizontal visualization of the skin at a nearly histological resolution and is currently a validated instrument for noninvasive diagnosis of skin tumors, already counting over 600 indexed articles. 4-15 Up-to-date, retrospective analyses 4-8,11-15 have demonstrated the capability of RCM to improve the diagnostic accuracy in skin cancer detection when combined with dermoscopy, but, to our knowledge, only 2 studies 16,17 have evaluated prospectively the real impact of RCM in the routine clinical workflow. These 2 articles assessed the reduction in number of lesions needed to excise to diagnose an MM achievable through RCM: lesions considered for the analysis were defined under the umbrella of "clinically and/or dermoscopically equivocal." However, this term encompasses a wide group of clinical and dermoscopic situations and does not provide clinicians with the best indications for referring patients to a tertiary center equipped with confocal microscopy for confocal analysis. To define the best indications for the use of RCM in daily practice, we prospectively evaluated the clinical and IMPORTANCE Reflectance confocal microscopy (RCM) improves diagnostic accuracy in skin cancer detection when combined with dermoscopy; however, little evidence has been gathered regarding its real impact on routine clinical workflow, and, to our knowledge, no studies have defined the terms for its optimal application. OBJECTIVE To identify lesions on which RCM performs better in terms of diagnostic accuracy and consequently to outline the best indications for use of RCM. DESIGN, SETTING, AND PARTICIPANTS Prospectively acquired and evaluated RCM images from consecutive patients with at least 1 clinically and/or dermoscopically equivocal skin lesion referred to RCM imaging, from January 2012 to October 2014, carried out in a tertiary referral academic center. MAIN OUTCOMES AND MEASURES A total of 1279 equivocal skin lesions were sent for RCM imaging. Spearman correlation, univariate, and multivariate regression models were performed to find features significantly correlated with RCM outcome. RESULTS In a total of 1279 lesions in 1147 patients, RCM sensitivity and specificity were 95.3% and 83.9%, respectively. The number of lesions needed to excise to rule out a melanoma was 2.4. After univariate and multivariate regression analysis, head and neck resulte...