The product of the MTS1/CDKN2 gene (p16) and the retinoblastoma protein (pRB) inhibit cell cycle progression at the late G1 checkpoint. The absence of functional p16 or pRB has been identified in a variety of human tumors but has not been well studied in mesenchymal neoplasia. Using an immunohistochemical approach, the authors identified abnormal expression of either p16 or RB in 16 and 14 of 59 sarcomas, respectively, for an overall abnormality rate of 51%. Specific rates of abnormality varied by histological subtype, with leiomyosarcomas most commonly affected by loss of either tumor-suppressor gene product. There was no significant correlation between p16 or RB expression and overall grade, mitotic grade, or tumor progression for sarcomas. In contrast, no fibromatoses and other spindle cell neoplasms of low malignant potential displayed abnormal p16 expression, and only 4 of 23 cases showed loss of pRB expression. These data show that aberrant expression of p16/pRB is one of the most common molecular derangements in sarcomagenesis.