CD5 is a 67 KD glycoprotein receptor that is present on a variety of T lymphocytes and mantle zone lymphocytes and is used routinely for the diagnosis of lymphomas and thymic carcinomas. That CD5 may be useful in diagnosis of mesenchymal tumors was an incidental finding in our sarcoma practice. This pilot study evaluated CD5 expression in benign and malignant muscle tumors in comparison to normal muscle. Search of our pathology database identified the following cases: leiomyomas (10), rhabdomyomas (3), leiomyosarcomas (33), and rhabdomyosarcomas (9). In some of these cases, non-neoplastic smooth muscle (10) and skeletal muscle (6) were identified adjacent to tumors. In addition, 3 cases were retrieved for non-neoplastic smooth muscle tissue that was unrelated to any tumor. Immunohistochemical analysis was performed on formalin-fixed paraffin-embedded tissue blocks using a CD5 monoclonal antibody. Positive immunoreactivity to CD5 was determined as 2+ (moderate) to 3+ (strong) cytoplasmic brown staining. CD5 was strongly and diffusely expressed in non-neoplastic skeletal (6/6) and smooth (10/10) muscle adjacent to tumor. Focal areas of moderate staining were sometimes observed. CD5 was also strongly and diffusely expressed in 3 cases of smooth muscle tissue not adjacent to tumor. Immunoreactivity to CD5 was negative in rhabdomyomas (3/3), rhabdomyosarcomas (9/9), and high-grade leiomyosarcomas (27/27 cases). Leiomyomas (10/10) were CD5 positive but showed variable intensity within the same tumor. Low-grade leiomyosarcomas (6/6) exhibited variable CD5 expression. In conclusion, this pilot study suggests that CD5 staining may be used to differentiate benign muscle tissue from malignancy. Albeit our case series is limited, this study indicates potential utility of CD5 staining in diagnosis of muscle tumors.