Purpose <p>The majority of patients with HNSCC primarily treated with (chemo)radiation receive bilateral elective nodal irradiation(B-ENI). However, this concept has shown to result in a considerable toxicity and deterioration of quality-of-life. We report on the technical feasibility of a SPECT/CT-based sentinel node procedure (SNP) approach to select patients for unilateral ENI (U-ENI).</p> Patients and methods <p>The primary tumor of 90 patients with lateralized T1-4N0-3 (N2c excluded) carcinoma of oropharynx, larynx and hypopharynx were injected under local anesthesia with indocyanine green (ICG)-^99mTechnetium(Tc)-nanocolloid, 3–4 h later SPECT/CT was done for lymph drainage mapping (LDM). Patients without contralateral drainage (CLD) received U-ENI and those with CLD received SNP. Patients with negative SN still received U-ENI while those with positive SN received B-ENI. Endpoints: contralateral regional failure and toxicity.</p> Results <p>Of the entire group, 82% had oropharyngeal cancer, 83% T1-2, and 77% Node-positive disease. LDM was successful in all patients. Flexible laryngoscope with working channel was used for the peri-tumoral injection in 53% of patients. Only 6 patients experienced the procedure as uncomfortable/painful. CLD was seen in 41 patients (45.5%), mainly in level II (63.4%). All of them received SNP and only 8 patients had positive SLN (19.5%), 7 of which in level II. These patients received B-ENI and the other 82 patients (91%) U-ENI. There was only one minor surgical complication (postoperative bleeding).</p> Conclusions <p>The SPECT/CT-based SNP to guide U-ENI is feasible, safe and has resulted in significant increase in proportion of patients treated by U-ENI. The results of oncologic outcome and toxicity need to be awaited.</p>