INTRODUCTION: Reliable staging of the neck remains a diagnostic challenge in head and neck squamous cell carcinoma (HNSCC) patients. Monoclonal antibodies (MAbs) directed against tumour-associated antigens can be used for selective tumour targeting. When labelled with a γ-emitting radionuclide like 99mTechnetium, such MAbs can be used for tumour detection by radioimmunoscintigraphy (RIS). OBJECTIVE: The aim of this study was to assess the potential of RIS for the detection of lymph node metastases in HNSCC patients. PATIENTS AND METHODS: In 49 patients with HNSCC, who were scheduled to undergo surgery including neck dissection, RIS using 99mTc-labelled squamous cell specific MAb E48 or U36 administered intravenously was compared with clinical palpation, computed tomography (CT), magnetic resonance imaging (MRI) and histopathological outcome. RESULTS: RIS detected lymph node metastases in 35 of 51 positive sides (sensitivity 69%). Interpretation of RIS was correct in 47 of 65 sides (accuracy 72%). Accuracy of palpation, CT and MRI were comparable. Immunohistochemical staining of lymph node metastases missed by RIS showed that the injected MAb had targeted these small tumour deposits but these were not visualized. CONCLUSIONS: RIS at its current stage of development is not superior to CT or MRI for the detection of lymph node metastases. As small tumour deposits were probably not visualized because of the limited sensitivity and/or spatial resolution of the gamma camera, positron emission tomography (PET) using MAbs labelled with positron emitters may improve the detection. As MAb-PET studies in an animal model showed promising results we will soon start a clinical MAb-PET study.