Here we report for the first time the radioactive labeling of gold nanoshells with 64Cu and 111In. A conjugation method was developed to link nanoshells with the radioactive tags. The resulting conjugates showed good labeling efficiency and stability in PBS and serum for in vivo imaging applications. The circulation of 64Cu-nanoshells and 111In-nanoshells in mice were determined by dynamic light scattering and their blood clearance in rats were determined in terms of radioactive counting. By PET/CT and SPECT/CT imaging, we monitored the in vivo distribution of 64Cu-nanoshells and 111In-nanoshells in nude rats with a head and neck squamous cell carcinoma xenograft at various time points after their intravenous injection. PET and SPECT images of the rats showed that both of the labeled nanoshells accumulated in the tumor. PET images with 64Cu showed better resolution and were therefore, more promising for future applications.