Background: The presence of multiple Lugol-voiding lesions (LVLs) in the esophageal mucosa can indicate a high risk of esophageal squamous cell carcinoma (ESCC) as well as a diagnosis of ESCC and dysplasia. However, there have been no reports on the natural course of LVLs. Aim: This study aimed to clarify the characteristics and natural course of LVLs. Methods: Based on patients with ESCC who underwent endoscopic treatment, a retrospective study was conducted targeting 73 patients in whom the esophageal background mucosa was evaluated using Lugol staining and who were followed up for 12 months or more. LVLs were divided into groups A (none), B (several small), C (many small), and D (many irregular-shaped multiform). Results: The average follow-up period was 42.0 months. Groups A–D consisted of 13, 34, 21, and 5 patients, respectively. In group B, 3 of 34 (8.8%) patients advanced to group C. In group C, 2 of 21 (9.5%) patients advanced to group D. In total, 5 of all 73 (6.8%) patients advanced to a higher group. Conclusion: These data suggest that a risk of ESCC may obviously increase in only some of the patients by evaluation of LVLs.