OBJECTIVE:: In a phase I/II clinical study, we investigated tumor targeting in patients with head and neck squamous cell carcinomas (SCC), using an antibody directed against the extra-domain-B of fibronectin (EDB), a marker of angiogenesis and tissue remodeling. STUDY DESIGN AND SETTING:: Five patients with SCC were injected with the -iodine-radiolabeled L19(scFv)2 antibody and underwent scintigraphic detection with single photon emission tomography with computerized tomography (SPECT/CT). In addition, F-fluorodeoxyglucose (FDG) positron emission tomography with computerized tomography (PET/CT) was performed. RESULTS:: Successful targeting of the primary tumor could be achieved in 4 of 5 patients and was comparable to PET imaging. No side effects were observed. CONCLUSIONS:: Tumor targeting with the L19(scFv)2 antibody is also feasible for head and neck SCC. SIGNIFICANCE:: These results may serve as a base for future therapeutical applications in human beings, with modified versions of the L19(scFv)2 antibody, designed to selectively deliver bioactive molecules into malignant tumors.