Sentinel lymph node biopsy has been shown to be highly accurate for detecting metastatic diseases, such as melanoma and breast cancer. Gamma probes that measure only the relative presence of radioactivity are commonly used to identify sentinel lymph nodes. We have developed a small semiconductor gamma camera (SSGC) that allows the size, shape, and location of the target tissues to be visualized. The purpose of this study is to characterize the performance of the SSGC for radioguided surgery of metastatic lesions and for diagnosing other diseases amenable to the smaller- format associated with this prototype imaging system. Methods & Design: The detector head was comprised of a 32 x 32 Cadmium Telluride semiconductor array and application- specific integrated circuit (ASIC) with a tungsten collimator. The entire assembly was encased in a lead housing measuring 152 mm x 166 mm x 65 mm. The effective visual field was 44.8 mm x 44.8 mm. Two spherical 5 mm diameter Tc-99m radioactive sources having activities of 0.15 MBq and 100 MBq were used to simulate sentinel lymph nodes and injection site. The relative detectability of these foci was compared using the new detector and a conventional scintillation camera. Use of the prototype was also explored on patients in a variety of clinical applications. Results: the SSGC provided better spatial resolution on phantom studies than the conventional gamma camera control. Both foci could be visualized clearly by the SSGC using a 15 second acquisition time, whereas they could not be readily identified using the conventional system under comparable conditions. Preliminary clinical tests of the SSGC were found to be successful in imaging diseases in a variety of tissues including salivary and thyroid glands, temporomandibular joints, and sentinel lymph nodes. Conclusion: The SSGC has significant potential for use in diagnosing diseases and for facilitating subsequent radioguided surgery. (This project was supported by a Grant- in-aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan).