Mutations in the gene encoding cartilage oligomeric matrix protein (COMP) cause two common skeletal dysplasias, pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED). At present, diagnosis of these diseases is based primarily on clinical and radiographic findings and is sometimes erroneous, particularly in adult patients. However, genetic diagnosis is difficult, because COMP mutations are scattered throughout the gene and five additional disease genes for MED exist. There is evidence that circulating COMP may serve as a molecular indicator of a variety of diseases affecting cartilage. Therefore, we investigated plasma COMP concentrations in 21 patients with PSACH or MED. Of these, six PSACH and seven MED patients carried COMP mutations, and the remaining eight MED patients lacked mutations in COMP. We observed significantly decreased plasma COMP levels in patients with COMP mutations compared with controls (P < 0.0001). In addition, plasma COMP levels were significantly decreased in MED patients carrying mutations in COMP relative to those who lacked COMP mutations (P = 0.001). Our results indicate that circulating COMP levels reflect genetic abnormalities in COMP, providing an easier, more rapid and cost-efficient method for diagnosing PSACH and particularly for MED.