Radiofrequency ablation (RFA) is an accepted treatment for flat Barrett’s neoplasia. Less is known about RFA for esophageal squamous cell neoplasia (ESCN). Our group has reported several prospective studies of RFA for ESCN in China with promising results through 12 months of follow-up. In this cohort study we aimed to evaluate longer term outcomes after RFA for ESCN. Patients with flat unstained lesions (USLs) on Lugol’s endoscopy containing moderate-/high-grade intraepithelial neoplasia (MGIN/HGIN) or mucosal cancer were treated with RFA every 3 months until complete remission (CR; no MGIN or a worse histologic grade). Patients with CR at 12 months (CR12) were included for follow-up and underwent annual Lugol’s endoscopy with biopsy sampling and re-RFA for flat USLs. The clinical course of patients with persistent ESCN at 12 months (treatment failures) is also reported. Among the 78 patients in CR12, 67 (86%) had sustained CR during a median of 48 months (interquartile range, 48-48) of follow-up and 5 endoscopies (interquartile range, 4-6). Recurrence occurred in 7 of 78 patients (9%; MGIN, n = 6; HGIN, n = 1); all lesions were managed with RFA. Four other patients (5%) had progression (to HGIN, n = 1; submucosal esophageal squamous cell carcinoma, n = 3). During follow-up protocol violations occurred in 46 of 78 patients (59%). Of the 12 treatment failures, progression occurred in 6. Overall, 2 patients developed subepithelial disease that was not visible after Lugol’s endoscopy. Based on post-hoc analysis, the pink-color sign at baseline (a pink color change after Lugol’s endoscopy) significantly predicted failure after RFA. RFA is relatively easy to apply and can efficiently treat large areas with ESCN. Despite protocol violations that may have interfered with the efficacy of RFA in 59% of patients, most patients with CR12 had sustained CR during follow-up. However, some patients progressed to advanced disease and 2 developed subepithelial disease, not visible after Lugol’s endoscopy. Based on currently available data, we advise the restriction of the use of RFA for flat MGIN and HGIN without the pink-color sign on Lugol’s chromoendoscopy. (Clinical trial registration number: NCT02047305.)