Evidence that early members of the classic pathway of complement are involved in the interaction of collagen with the blood platelet is presented. C4 is required for platelet aggregation response to low concentrations of fibrous collagen but not for adhesion of collagen to platelets obtained from guinea pigs genetically lacking C4. The aggregation response is restored, however, by preincubation with either C4 or normal plasma. It is suggested that membrane-bound C1s is the receptor site for collagen, inasmuch as preincubation of normal platelets with antiserum to C1q specifically enhances the platelet-collagen interaction, demonstrating a potential competition between C1q and collagen for the platelet binding site. This concept is further supported by the fact that C1s inhibitors also enhance aggregation response to collagen. Under physiologic conditions, the role of complement in the platelet response to collagen should be highly significant.