A 56 residue fragment derived from a Waldenstrom IgM protein and consisting of 24 residues of the amino terminal portion of the Cμ4 domain disulfide bonded to 32 residues of the carboxy terminal region of the loop has been shown to fix active C1 (C1) in a C1 fixation assay. Cleavage of the disulfide bond within the C(H)4 fragment resulted in a marked decrease of C1 fixing ability, although the isolated A and B fragments did retain a limited ability to fix C1 Upon incubation with normal human serum the intact C(H)4 fragment and equal molar amounts of the isolated A and B peptides consumed C4 suggesting that the C1 activating determinant of IgM remains intact in these three fragments. Furthermore, on a molar basis the intact or the reduced C(H)4 fragment consumed C4 as effectively as each of its component chains, suggesting that transient binding of C1 by the individual A and B peptide chains is sufficient to activate C1. On the basis of these observations it is proposed that a classical complement fixation function, i.e. C1 binding and activation, can be localized within a region of the IgM molecule corresponding to the Cμ4 domain.