Background and Aims Surveillance programs of patients with head and neck cancer (HNC) detect synchronous or metachronous esophageal squamous cell carcinoma (ESCC) in up to 15% of patients. Noninvasive, probe-based confocal laser endomicroscopy (pCLE) technique may improve the diagnosis allowing acquisition of high-resolution in vivo images at the cellular and microvascular levels. The aim of this study was to evaluate the accuracy of pCLE for the differential diagnosis of nonneoplastic and neoplastic Lugol-unstained esophageal lesions in patients with HNC. Methods Twenty-seven patients with HNC who exhibited Lugol-unstained esophageal lesions at surveillance endoscopy were prospectively included for pCLE. Diagnostic pCLE was followed by subsequent biopsies or endoscopic resection of suspected lesions. A senior pathologist was blinded to the pCLE results. Results Patients mean age was 59 years (SD = 8.8) and 70.4% were men. All patients were smokers, and 22 patients (81.5%) had a history of alcohol consumption. The locations of HNC were oral cavity (n = 13), larynx (n = 10), and pharynx (n = 4). Thirty-seven lesions in 27 patients were studied. The final diagnoses were ESCC in 17 patients and benign lesions in 20 patients. Sensitivity, specificity, and accuracy of pCLE for the histologic diagnosis of ESCC in patients with HNC were 94.1%, 90.0%, and 91.9%, respectively. Conclusions First, pCLE is highly accurate for real-time histology of Lugol-unstained esophageal lesions in patients with HNC. Second, pCLE may alter the management of patients under surveillance for ESCC, guiding biopsies and endoscopic resection, avoiding further diagnostic workup or therapy of benign lesions.