Complement C2 receptor inhibitor trispanning (CRIT) inhibits the classical pathway (CP) C3 convertase formation by competing with C4b for the binding of C2. The C-terminal 11-amino-acid of the first CRIT-extracellular domain (CRIT-H17) has a strong homology with a sequence in the C4 beta chain, which is responsible for the binding of C2. Since the CP and alternative pathway (AP) C3 convertases have many functional and structural similarities, we further investigated the effects of CRIT-H 17 on the AP. The factor D-mediated cleavage of factor B (FB) was blocked by CRIT-HIT By ELISA and immunoblot, CRIT-H17 was shown to bind FB. CRIT-H 17 had no decay activity on the C3bBb complex as compared to decay-accelerating factor. Binding of CRIT-H 17 to FB did not interfere with the assembly of C3bB complex. In a haemolytic assay using C2-deficient serum, CRIT-H17 interfered with AP complement activation. (c) 2006 Elsevier Inc. All rights reserved.