Pseudoxanthoma elasticum (PXE) is a hereditary disorder of the connective tissue characterized by extracellular matrix alterations with elastin fragmentation and excessive proteoglycan deposition. Xylosyltransferase I (XT-I, E.C. 2.4.2.26) is the initial enzyme in the biosynthesis of the glycosaminoglycan chains in proteoglycans and has been shown to be a marker of tissue remodeling processes. Here, we investigated for the first time serum XT-I activities in a large cohort of German PXE patients and their unaffected relatives. XT-I activities were measured in serum samples from 113 Caucasian patients with PXE and 103 unaffected first-degree family members. The occurrence of the frequent ABCC6 gene mutation c.3421C>T (R1141X) and the hypertension-associated genetic variants T174M and M235T in the angiotensinogen (AGT) gene were determined. Serum XT-I activities in male and female PXE patients were significantly increased compared to unaffected family members (male patients, mean value 0.96 mU/l, SD 0.37; male relatives, 0.78 mU/l, SD 0.29; female patients, 0.91 mU/l, SD 0.31; female relatives, 0.76 mU/l, SD 0.34; p<0.05). The mean XT-I activities in PXE patients with hypertension were 24% higher than in patients without increased blood pressure (p<0.05). The AGT T174M and M235T frequencies were not different in hypertensive PXE patients, normotensive PXE patients, family members or blood donors. Our data show that the altered proteoglycan biosynthesis in PXE patients is closely related to an increased XT-I activity in blood. Serum XT-I, the novel fibrosis marker, may be useful for the assessment of extracellular matrix alterations and disease activity in PXE.