Well-differentiated thyroid carcinoma (WDTC) has a high predilection for regional metastatic spread. Rates for WDTC lateral neck recurrence are reported to be as high as 24% in patients after initial thyroidectomy, lateral neck surgery, and adjuvant radioactive (RAI) iodine treatment. The objective of the study was to evaluate the efficacy, safety, and long-term outcome of comprehensive lateral neck dissection (LND) of levels II-V for recurrent or persistent WDTC in a tertiary referral center. This study retrospectively analyzed the standardized approach of LND for recurrent WDTC in the lateral neck compartment. Survival was analyzed by Cox regression analysis. Three hundred and seven patients underwent 429 LND for cytopathology-confirmed lateral neck recurrent WDTC at the University of Texas MD Anderson Cancer Center between 1994 and 2012. The vast majority (90%) of patients were originally treated elsewhere. Multilevel lateral neck dissection had been originally performed in 80% of patients, with 17% having undergone at least two previous operations. Two hundred and sixty-seven (87%) patients had previous RAI. The most common levels of recurrence were levels III and IV (33% and 33%, respectively). Postoperative complications were seen in 7% of patients. Median follow-up was 7.2 years. In-field lateral neck control was 96% at 10 years. Overall lateral neck regional control, overall survival (OS), and disease-specific survival (DSS) at 10 years was 88%, 78%, and 91%, respectively. When stratifying by age (<24 years, 24-50 years, and >50 years), OS and DSS was significantly better in patients <50 years (OS: p < 0.001; DSS: p < 0.001). However, there was worse overall lateral neck control in the younger group (<24 years; p = 0.04). Regional recurrence after salvage LND occurred within a median time interval of 20.0 months (2.9-121.3 months), of which 2% (8/429) developed in-field lateral neck recurrences. Of those with any lateral neck recurrence after salvage LND, 24/30 (80%) patients successfully underwent another LND, resulting in an ultimate 98% lateral neck regional control rate. Expert comprehensive LND of levels II-V is associated with few perioperative complications and results in very high in-field regional control rate and ultimate lateral neck control in recurrent/persistent WDTC.