Serum immunoreactive prolyl hydroxylase protein and galactosylhydroxylysyl glucosyltransferase activity were measured in 54 patients wtih various dermatological diseases and compared with corresponding values in 32 control subjects. These serum enzymes were at the control level in the great majority of the patients, and no correlation was found between serum and skin enzymes, except for one weak correlation in lichen ruber planus. Some patients with psoriasis, lichen ruber planus, keloids, erythema nodosum or chronic discoid lupus erythematosus, however, did have at least one of these enzymes elevated in the serum, and a significant correlation (P less than 0.01) between the two enzymes was found in the total disease material. Thus it does seem that diseases limited only to the skin can sometimes raise these serum enzyme levels. The mean levels of serum immunoreactive prolyl hydroxylase and galactosylhydroxylysyl glucosyltransferase activity were significantly elevated (P less than 0.001) in active systemic connective tissue diseases such as systemic lupus erythematosus, scleroderma or dermatomyositis compared with the controls, and 4 out of 7 values for immunoreactive prolyl hydroxylase and 3 out of 7 for galactosylhydroxylysyl glucosyltransferase activity were above the 95% confidence limit of the controls. Since the levels of the skin enzymes were not elevated in most of these patients, however, the main sources for the elevated serum enzymes were probably tissues other than the skin.