Interactions between C-reactive protein (CRP) and liposomal model membranes containing phosphatidylcholine were investigated. These interactions, in the presence of human serum, resulted in consumption of each of the components of the classical complement pathway (C1-C9) and also resulted in complement-dependent damage and release of trapped glucose from certain types of liposomes. CRP-initiated lysis of liposomes was strongly dependent upon membrane lipid composition. Optimal activity occurred with positively charged liposomes containing galactosylceramide (galactocerebroside); positively charged liposomes lacking galactocerebroside released much less glucose, while negatively charged liposomes, either with or without galactocerebroside, did not release glucose at all. Glucose release was inhibited by free phosphocholine. Lesser, but significant, "background" glucose release independent of the presence of CRP also was observed with positively charged liposomes containing galactocerebroside, and this was associated with marked preferential consumption of the later-acting complement components (C3-C9). C2-deficient human serum failed to support CRP-dependent glucose release, but glucose release was observed upon reconstitution of the serum with C2. Guinea pig complement also did not support CRP-mediated glucose release, but upon addition of human C1q substantial glucose release was observed. We conclude that (i) CRP can sensitize appropriate liposomes for complement-dependent damage via the primary complement pathway starting at the level of C1q; (ii) of those studied, liposomes that are most susceptible to membrane damage contain phosphatidylcholine, have a positive charge, and contain a ceramide glycolipid; and (iii) such liposomes also are sensitive, although to a much lesser degree, to complement-dependent lysis initiated in the absence of CRP and involving consumption of terminal in excess of early acting complement components.