The HMGIC gene, which codes a protein that acts as an architectural transcription factor, is frequently rearranged in a variety of benign or locally aggressive mesenchymal tumors. In tumors of smooth muscle differentiation, only uterine leiomyoma and lipoleiomyoma are known to be associated with the altered HMGIC. We investigated molecular and genetic alterations of the HMGIC in 36 benign and malignant smooth muscle tumors arising at various anatomical sites, including 13 uterine leiomyomas, two leiomyomas of the kidney with a t(12;14), one pelvic lipoleiomyoma, one vascular leiomyoma of the foot, two uterine leiomyosarcomas, six retroperitoneal leiomyosarcomas, one leiomyosarcoma of the urinary bladder, and 10 leiomyosarcomas of external soft tissues. HMGIC gene expressions were detected in both uterine (73.3%) and extrauterine (57.1%) smooth muscle tumors by reverse transcriptase polymerase chain reaction (RT-PCR), and benign tumors (70.5%) more frequently expressed the HMGIC than leiomyo-sarcomas (57.8%). Variant transcripts of the HMGIC containing cryptic exonic sequences previously described were found in one renal and three uterine leiomyomas and four leiomyosarcomas arising in the uterus and soft tissues by RT-PCR. Southern blot analysis identified a rearranged HMGIC in one soft tissue leiomyosarcoma. Thus, the HMGIC alterations in smooth muscle tumors are not confined only to uterine leiomyoma or lipoleiomyoma. Our data expand the variety of mesenchymal tumors associated with HMGIC alterations.