Mseleni joint disease (MJD) is an unusual form of progressive and widespread degenerative osteoarthropathy that has been identified in several hundred people in the remote Mseleni region of northern Zululand. Affected individuals experience articular discomfort in childhood and may be seriously handicapped as adults, often requiring prosthetic hip joint replacement. Although the condition clusters in families, there is no evidence of Mendelian inheritance and assessment of affected kindreds has not shown any evidence of genomic imprinting. To date our molecular work-up has entailed the study of 47 affected individuals from MJD kindreds to investigate familial predisposition based on the inheritance of a subset of markers and/or genes on the human genome, particularly those associated with the cartilage matrix. In addition, we have collected blood specimens form 111 unaffected but unrelated individuals from the same population group in order to determine whether any relationship exists between genetic components of the human leucocyte antigen (HLA) system and the MJD phenotype. Our investigations show the following: (i) there is no association between MJD and the HLA system which has previously been associated with non-Mendelian genetic conditions; (ii) COL2A1, which has been implicated in some forms of spondylo-epiphyseal dysplasia, may be involved in at least a subset of MJD patients; and (iii) type VI collagen is overabundant in degenerated hip joint cartilage.