Severe psoriasis is associated with significant cardiovascular mortality. We therefore investigated the effects of systemic therapy on the cardiovascular risk of psoriasis patients. Thirteen consecutive patients receiving fumaric acid esters were included and followed for 24 weeks both clinically and by means of laboratory monitoring, 10 completed the study. Eight of ten patients showed a PASI-50 response. Two of three patients with clinical insulin resistance (Homeostasis Model Assessment of insulin resistance >2.5) showed normal insulin responsiveness at the end of the study. Clinical improvement was paralleled by a reduction of high-sensitive CRP serum levels (median -25%). There was a trend toward reduced serum levels for the vascular endothelial growth factor (median -10%) and resistin (median -4%), while the potentially cardio-protective adiponectin showed a trend toward increased serum levels under therapy (median +19%). Systemic endothelial function assessed by venous occlusion plethysmography revealed an improvement of endothelial vasodilator function after 24 weeks of treatment (p < 0.02). This is the first prospective study documenting an amelioration of endothelial cell function in patients with moderate-to-severe plaque-type psoriasis under effective continuous systemic therapy. Future studies need to compare the cardioprotective effects of different treatment modalities, based on hard end points such as the rate of myocardial infarction.