OBJECTIVE Six cases of adventitial cystic disease were studied, and the existing theories of the aetiology of adventitial cystic disease were reviewed to present evidence in support of a variation of the developmental hypothesis that might explain the sites of occurrence of this rare condition. METHODS Cases of adventitial cystic disease were collected by interrogation of the records of a group of vascular surgeons in the Johannesburg area. After reviewing the relevant literature, the sites of occurrence of 323 cases of adventitial cystic disease were documented, and the theories of the formation of adventitial cystic disease were reviewed. The embryological origin of those vessels in which adventitial cystic disease occurs was investigated. Clinical cases were collected in private practice vascular referral centers. The clinical features, treatment, and subsequent course of six cases of adventitial cystic disease (four related to the popliteal artery, one in the femoral artery, and one in the radial artery) are included. RESULTS All cases of adventitial cystic disease reported have occurred in the nonaxial arteries, which form at a later stage than the axial vessels during limb differentiation and development. It is therefore postulated that during limb bud development cell rests derived from condensations of mesenchymal tissue destined to form the knee, hip, wrist, or ankle joints are incorporated into the nearby and adjacent nonaxial vessels during development of these vessels in the 15-22-week stage. These newly forming nonaxial vessels develop from vascular plexuses during the same stage of development, and in close proximity to the adjacent condensing joint structures. It is further postulated that these cell rests are then responsible for the formation of adventitial cystic disease later in life, when the mucoid material secreted results in a mass lesion within the arterial or venous wall. CONCLUSIONS There is evidence supporting the hypothesis that adventitial cystic disease is a developmental condition occurring in the nonaxial blood vessels.