Cartilage oligomeric matrix protein (COMP) is an extracellular matrix protein expressed in cartilage, ligament, and tendon. The importance of COMP in the matrix of these cells is underscored by the discovery that mutations in COMP cause the skeletal dysplasias, pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (EDM1). Here, we present the first report on the analysis of the human COMP promoter region in cartilage, ligament, and tendon cells. A 1.7-kb region of the COMP promoter has been cloned and sequenced and no TATA or CAAT boxes were found. Primer extension identified multiple transcription start sites. All four transcription start sites were utilized in chondrocytes with only three of them utilized in tendon and ligament cells. Differential regulation was observed for different parts of this 1.7-kb region with the 370-bp proximal region conveying the strongest promoter activity. The highest activity was observed in tendon and ligament. Finally, we provide evidence that the DNA binding protein SP1 plays a role in the regulation of COMP expression. These results indicate that COMP expression within these cells is regulated in a unique manner that differs from the expression of other extracellular matrix genes.