Soft tissue sarcomas represent a heterogeneous group of mesenchymal malignancies, and the majority of the previous scientific studies that have analyzed the occurrence of cell cycle regulators aberrations within soft tissue sarcomas have dealt with broad categories of different tumors. As a consequence, data concerning single classes of sarcomas are very limited. The authors analyze herein a histologically homogeneous series of 23 cases of leiomyosarcoma of the deep soft tissue. The p53 pathway was studied by investigating the p53 gene and protein, MDM2 protein, and p21waf1 protein. The Rb-cyclin D pathway was analyzed by studying the Rb gene and protein, p16MTS1/INK4A gene and protein, cyclin D1Prad1/bcl1 and cyclin D3 proteins. Aberrations of the p53 pathway were observed in about 16 percent of cases and were limited to the p53 gene. Such a finding contrasts with the higher rates of p53/MDM2 abnormalities reported in other types of sarcomas such as liposarcoma. Interestingly, abnormalities involving the Rb-cyclin D pathway were detected in about 90 percent of cases. The Rb-cyclin D pathway therefore emerges as the preferred target for molecular abnormalities in this subset of soft tissue sarcomas.