BACKGROUND: Lateral lymph node (LLN) metastasis is a major cause of local recurrence of advanced rectal cancer. Although there is much controversy between Western and Eastern countries on whether lateral pelvic lymph node dissection (LLND) or neoadjuvant chemo-radiation (nCRT) is preferable for the treatment of LLN metastases, existing retrospective cohorts mainly focus on all middle/low advanced rectal cancer patients, not the specific individuals with suspicion of LLN metastases. The aim of this trial is to assess the efficacy and safety of LLND for rectal cancer patients with suspicion of LLN metastases. METHODS: This prospective, multicenter, randomized controlled, single-blinded, phase III trial is designed to enroll 512 eligible patients with advanced rectal cancer and preoperative enlarged lateral lymph nodes. The population will be randomly assigned into the solely total mesorectal excision (TME) group or the TME + LLND group after eligible selection. The primary outcomes are to be 3-year local recurrence rate and 3-year disease-free survival, and the secondary outcomes include 3-year overall survival, 1-year sexual and urinary function, and perioperative outcomes. DISCUSSION: This is the first randomized trial to investigate the efficacy and safety of LLND for advanced low rectal cancer patients with suspicion of LLN metastases; the result is expected to provide new evidence for the treatment of LLN where there is suspicion of metastases in advanced rectal cancer patients. TRIAL REGISTRATION: This trial was registered at ClinicalTrials.gov (identifier NCT02614157 ) Registered on 24 November 2015.