Pseudoxanthoma elasticum (PXE (OMIM #264800)) is an autosomal recessive connective tissue disorder mainly caused by mutations in the ABCC6 gene. PXE leads to ectopic calcification primarily in the skin, eye and blood vessels that may result in blindness and cardiovascular complications. We investigated the association between the skin morphology and systemic involvement in 25 confirmed PXE patients. Ex vivo multiphoton microscopic (MPM) imaging was performed to assess the extent of calcification. The area affected by calcification (CA) in the dermis and density of calcification (CD) was calculated. The number of involved skin sites typically affected by PXE and nontypical skin sites were counted. Extended Phenodex scores were determined. The correlation of the ophthalmological and cardiovascular complications and CA, CD and skin involvement was analysed. Regression models was used for adjustment to age, duration of the disease and sex. The number of typical skin sites showed correlation with the Phenodex score (ρ=0.55, p=0.004), Skin- score (r=0.75, p=<0.001), whereas the number of affected nontypical skin sites correlated with the Eye-score (r=0.4, p=0.047). We found significantly higher CA (p= 0.012) and CD (p=0.032) among patients with redundant skin folds. Also, significantly higher CD was observed in patients with inflammatory skin signs (p=0.039) and with internal carotid artery hypoplasia (p=0.045). There was a significant correlation between CA and the number of affected typical skin sites (r=0.44, p=0.026), aortic calcification (r=-0.44, p=0.027) and peripheral atherosclerosis (r=0.4, p=0.02). CD correlated significantly with the Vascular scores (r=0.45, p=0.022). To conclude, MPM may prove to be useful for the identification of PXE patients with high risk for more severe systemic complications.