The mechanism of complement depletion from human serum fortified with porphyrin and irradiated with light has been reinvestigated, with the conclusion that it did not depend on the normal sequence of complement activation. Thus, disappearance of the activities of C3, C4, and C5 was not dependent on divalent cations. Purified C3-C7 were labile to porphyrin/light treatment in the absence of other components. The depletion of C4 was not prevented by potent inhibitors of C1 and, unlike the depletion of C4 seen in response to aggregated gamma globulin, was insensitive to change in temperature. Electrophoresis showed an alteration of C3 unlike that caused by cobra venom factor and that light/porphyrin treatment nonspecifically altered many serum proteins.