Human C-reactive protein (CRP) is known to activate the C system upon reaction with phosphocholine-containing or polycation-containing ligands. We found that, even in the absence of these ligands, CRP caused C activation in mildly acidic conditions. The optimum pH for the activation was 6.3, which is within a physiologic range normally found at an inflammatory locus. In this activation, C components C1 and C4 were extensively consumed, C2 and C3 were moderately consumed, and C5 was only slightly consumed. These results indicate that the activation is mediated via the classical pathway, but is restricted to the early stage of the C cascade. As with the plasma contact system, the reaction proceeded in glass tubes but not in polypropylene tubes. However, even in polypropylene tubes, the reaction proceeded after the supplement of kaolin particles to the system. Probably the C activation induced by CRP at a mildly acidic pH required negatively charged surfaces. Analyses of circular dichroism and fluorescence spectra indicate that CRP undergoes a pH-dependent conformational change, thus affecting the reactivity of CRP with the C system.