In the present study two clinical isolates of S. pneumoniae from pneumococcal HUS-patients were investigated. Both clinical strains (SpHUSA and SpHUSB) express the Factor H-binding proteins, translation elongation factor Tu (Tuf) and pneumococcal surface protein C (PspC). In contrast to the highly conserved Tuf proteins, the PspC molecules of the clinical isolates have prominent sequence variations. SpHUSA expresses an isotype of subgroup PspC6. SpHUSB expresses a new variant of PspC3. Recombinant PspC of the clinical strains binds the human complement regulator Factor H. PspC-bound Factor H has cofactor activity and supports the Factor I-mediated inactivation of C3b. SpHUSA and SpHUSB recruit high amounts of Factor H to their surface and pneumococci-bound Factor H retains cofactor activity. Also complement-mediated opsonization and phagocytosis of the clinical isolates by human neutrophils is reduced. Thus, efficient Factor H binding improves the immune evasion of the clinical strains. Surface-bound Factor H increases adhesion of SpHUSA and SpHUSB to human, vascular endothelial cells and consequently their potential to damage host cells. The clinical strains bind high amounts of the complement regulator plasminogen. PspC is identified as new pneumococcal plasminogen-binding protein. PspC- and pneumococci-bound plasminogen can be converted to the serine protease plasmin by human activators and degrades C3b. Therefore, PspC-mediated plasminogen binding contributes to immune evasion of the clinical strains. Surface-bound plasmin damages human, vascular endothelial cells, induces the exposition of the subendothelial matrix and thereby causes a prothrombotic milieu. This may lead to the activation of thrombocytes and thrombus formation, inducing mechanical hemolysis, disturbance of renal function and thus the phenotype of pHUS. By that, the present study describes a connection of Plasmin-mediated damage of human, vascular endothelial cells and the pathogenesis of pHUS.