Addition of enzymatically active 125I-labeled Cls̄ (the esterase which is part of the activated complex protein of serum designated as the first component of complement or Cl̄) to purified C4 (the naturally occurring fourth component of human serum complement) results in binding of a portion of the Cls̄ to C4 as indicated by sucrose density gradient ultracentrifugation. Demonstration of binding requires hemolytically active C4, but not enzymatically active Cls̄. The latter was demonstrated by using DFP inactivated Cls̄ as well as fragments of Cls̄ produced by prior protease treatment of the Cls̄. While treatment of Cls̄ with proteases (human leukocyte lysosomal enzymes, trypsin or plasmin) resulted in progressive inactivation of the enzymatic activity, the decline in esteratic activity occurred at a much slower rate than the decline in functional activity (inactivation of C4 in free solution). The data lead to the probable conclusion that Cls̄ contains an enzymatic (or esteratic) site in addition to a binding site. The latter might be important for positioning a large molecule, such as C4, in order to effect proteolytic cleavage at the proper bond and hence prepare C4 to participate in the complement sequence.