Systemic sclerosis (SSc) is characterised by ischemic damage, impaired angiogenesis and skin fibrosis. Tissue kallikrein (t-kallikrein) is involved through kinins in inflammation, vasorelaxation and angiogenesis. T-kallikrein is synthetised by endothelial, smooth muscle, and inflammatory cells and, in skin, also by dark cells of the sweat glands, where it is involved in sweat formation. Our aim was to analyse, by immunohistochemistry and RT-PCR, the expression of t-kallikrein in the skin of patients with different SSc subsets, limited (lSSc) and diffuse (dSSc), and phases, early and advanced. Skin biopsies were taken from 18 SSc patients and 10 controls. Immunohistochemistry was performed on paraffin sections with an antibody against human urinary t-kallikrein. For RT-PCR, cDNA from skin biopsies was amplified using primers specific for human t-kallikrein. In the control skin, dark cells of the secretory units of sweat glands showed immunopositivity for t-kallikrein as well as blood vessels. In the lSSc skin, immunoreactivity was observed only in some glands, with weak staining in the advanced phase. In early lSSc skin, immunoreactivity was observed in microvessel walls and in the inflammatory infiltrate. In dSSc skin, dark cells of the glandular fundus units, and the few remaining vessels showed scarcity (early phase) or lack (advanced phase) of immunoreactivity for t-kallikrein. RT-PCR confirmed a decrease of t-kallikrein mRNA levels from early to advanced phase in SSc subsets, reaching its lowest level in advanced dSSc. In conclusion, immunohistochemical and biomolecular results indicate that t-kallikrein is decreased in the skin of SSc patients and decreases progressively from the early to advanced phase of lSSc and dSSc. The decreased expression of t-kallikrein may be involved in the impairment of the sweating process, vessel functionality and angiogenesis.