Background: Chronic progressive lymphedema in Clydesdale and Shire draft horses causes severe disability of the limbs which leads to premature death of these horses. Since appropriate function of lymph vessels is dependent on the presence of viable elastin fibers, the goal of this study was to document differences in skin elastin fibers in affected horse breeds, compared to a nonaffected draft horse breed., Methods and Results: Biochemical analysis of cutaneous desmosine, a cross-linking amino acid found only in elastin, was used to measure elastin in the skin from 110 draft horses. This included 7 normal, 38 mildly affected, 30 moderately, and 15 severely affected horses, and 20 horses of a nonaffected draft breed. Desmosine concentrations in neck, considered a nonaffected skin region, and left forelimb, an affected skin region, were compared between the groups. A significantly lower desmosine concentration was found in the skin of the neck and limb of clinically normal animals of affected draft breeds compared to a nonaffected draft horse breed. During the progression of the disease in the affected breeds, cutaneous desmosine concentrations most prominently increased in the skin of the distal limbs., Conclusions: Chronic progressive lymphedema in draft horses was associated with an initially systemic lower cutaneous elastin level and a deposition of elastin during the progression of the disease. A failure of elastic fibers to appropriately support the skin and its lymphatics is proposed as a possible contributing factor for chronic progressive lymphedema in Shires and Clydesdales.