Widespread effort is being devoted to the search for a serologic "marker" that could aid in the early diagnosis of osteoarthritis and in following the progression of the disease in response to treatment. It is obvious that such a marker would have its greatest utility in patients with mild or early osteoarthritis. CMGP is a disulfide-bonded 550,000 dalton cartilage matrix glycoprotein with a half-life of only 48 to 72 hours that has been found, through immunolocation analysis, in the serum of dogs with experimentally induced osteoarthritis and in the synovial fluid of patients with osteoarthritis but not other types of arthritis. To determine whether detection of CMGP in serum might be of value in identifying patients with "early" osteoarthritis, we examined serum samples from 26 patients with knee pain who had articular cartilage lesions of osteoarthritis at arthroscopy but whose knee radiographs were normal or showed only mild or moderate osteoarthritis. CMGP was identified by immunolocation analysis with specific antibodies. Eleven patients (42%) were seropositive for CMGP. In two, the degenerative cartilage lesions visualized at arthroscopy were mild (grade 2); in the other nine they were more severe (grade 3 or 4). However, 10 of the 15 seronegative patients also had grade 3 or 4 cartilage degeneration. Thus, this serum assay for CMGP was often negative in this group of patients in the presence of well-defined cartilage degeneration.