Complement was proposed to play an important role in the onset of Multiple Sclerosis (MS) lesions by inducing physical damage to myelin-producing cells. Every somatic cell is however endowed with a repertoire of membrane-bound molecules which normally down-regulate the complement activation cascade (Regulators of Complement Activation, RCA) and therefore protect cells from complement-dependent lysis. We show here that antibodies against two complement regulatory molecules expressed in the membrane of human cells (CD46 and CD59) are present in sera from relapsing-remitting MS patients in the acute phase, that they are directed against the active site of the RCA molecules and that they inactivate their regulatory function, thus providing a mechanism by which cells of the nervous system might be damaged in a complement-dependent fashion during the acute MS phase. Moreover, we found that most of these sera also contain antibodies reacting with an epitope of the transmembrane glycoprotein of HIV which is conserved in most retroviruses; this may support the hypothesis that self-reacting antibodies might have arisen in these patients as an immune response after retroviral infection or expression of endogenous retroviral proteins.