h-Caldesmon (h-CD) is a protein combined with actin and tropomyosin that regulates cellular contraction. h-CD has been thought to be expressed exclusively in vascular and visceral smooth muscle cells (SMC). We examined h-CD expression immunohistochemically in tumors with SMC and SMC-like differentiation to clarify whether h-CD is specifically expressed in SMC tumors. The tumors examined in this study were six leiomyomas (LM), two angioleiomyomas (ALM), six leiomyosarcomas (LMS), eight rhabdomyosarcomas (RMS), eight malignant fibrous histiocytomas (MFH), four desmoids, three glomus tumors (GT), and two inflammatory myofibroblastic pseudotumors (IMP) of urinary bladder. We found that LM, ALM, LMS, and GT showed intense and extensive immunoreactivity for h-CD, whereas other tumors were completely negative for h-CD. In addition, h-CD was not present in the vascular pericytes and myofibroblasts, in contrast to actin. Although myoepithelial cells were immunopositive for h-CD, neoplastic myoepithelial cells of myoepithelial tumors and mixed tumors of the salivary gland and skin were all negative. These findings indicate that h-CD is a specific marker of both SMC and its neoplasms and that immunohistochemical detection of h-CD may facilitate the differential diagnosis between LMS and other tumors with SMC-like differentiation, including myofibroblastic tumors.