Background: There is variability in the literature on the role of the depth of invasion (DOI) for recommending an elective neck dissection (END). Purpose: The purpose of the study is to estimate the DOI threshold for recommending an END. Study Design, Setting, Sample: A retrospective cohort study was performed at McGill University Health Centre from 2008 to 2018 with 5 years of follow-up. The sample was subjects with clinical T1/T2 oral squamous cell carcinoma and clinically negative neck. Subjects with previous head and neck cancer were excluded. Predictor Variable: The primary predictor variable was DOI measured from the basement membrane of the adjacent normal mucosa on final pathology, coded as <4 mm or >= 4 mm. DOI is a continuous variable converted to a binary variable. Main Outcome Variable: The main outcome variable was time to development of neck disease (RD+) defined as the time from surgery to development of pathologic nodes. Time to RD+ for pathologic nodes discovered from the END was considered 0 months. The secondary outcome variable was overall survival. Covariates: Demographics (age, sex, and smoking/alcohol history) and tumor characteristics (tumor location, clinical T, tumor differentiation, perineural invasion, and lymphovascular invasion) were analyzed. Analyses: Time to RD+ and survival were analyzed using Cox hazard ratio, Kaplan-Meier curves, and log-rank test. Student's t-test and chi(2) test were used for bivariate analyses; P <= .05 was statistically significant. Results: The final sample were 64 subjects (average age 65.25 [standard deviation 13.06] years and 36 [56.2%] males). Twenty-nine subjects had DOI < 4 mm, and the 5-year RD+ was 3.4% (the 1 occurrence of RD+ was at 5.3 months). Thirty-five subjects had DOI >= 4 mm, and the 5-year RD+ was 45.7% (15 subjects had RD+ discovered from the END, and 1 subject had RD+ at 7.6 months). DOI >= 4 mm had significantly higher risk of RD+ than DOI < 4 mm (hazard ratio 17.91; 95% confidence interval 2.37 to 135.3; P = .01), which remained significant after adjusting for clinical T, tumor differentiation, perineural invasion, and lymphovascular invasion (hazard ratio 9.53; 95% confidence interval 1.12 to 81.44; P < .05). The shallowest DOI with >20% risk of RD+ was in the DOI 4 mm to 4.9 mm group. Conclusion and Relevance: Among patients with oral squamous cell carcinoma of T1 or T2 and clinically negative necks, END should be considered with DOI >= 4 mm. (c) 2025 The Authors. Published by Elsevier Inc. on behalf of the American Association of Oral and Maxillofacial Surgeons. This is an open access article under the CC BY-NC license (http:// creativecommons.org/licenses/by-nc/4.0/).