Sentinel node (SN) biopsy is accurate in operable oral and oropharyngeal cT1-T2N0 cancer (OC), but, to our knowledge, the oncologic equivalence of SN biopsy and neck lymph node dissection (ND; standard treatment) has never been evaluated.In this phase III multicenter trial, 307 patients with OC were randomly assigned to (1) the ND arm or (2) the SN arm (experimental arm: biopsy alone if negative, or followed by ND if positive, during primary tumor surgery). The primary outcome was neck node recurrence-free survival (RFS) at 2 years. Secondary outcomes were 5-year neck node RFS, 2- and 5-year disease-specific survival (DSS), and overall survival (OS). Other outcomes were hospital stay length, neck and shoulder morbidity, and number of physiotherapy prescriptions during the 2 years after surgery.Data on 279 patients (139 ND and 140 SN) could be analyzed. Neck node RFS was 89.6% (95% CI, 0.83% to 0.94%) at 2 years in the ND arm and 90.7% (95% CI, 0.84% to 0.95%) in the SN arm, confirming the equivalence with P < .01. The 5-year RFS and the 2- and 5-year DSS and OS were not significantly different between arms. The median hospital stay length was 8 days in the ND arm and 7 days in the SN arm (P < .01). The functional outcomes were significantly worse in the ND arm until 6 months after surgery.This study demonstrated the oncologic equivalence of the SN and ND approaches, with lower morbidity in the SN arm during the first 6 months after surgery, thus establishing SN as the standard of care in OC.