The purpose of this study was to examine the molecular parameters necessary for initiation of complement fixation by IgM proteins. To determine why some IgM molecules are capable of complement fixation while others are not, several different Waldenstrom IgM proteins were examined for their ability to fix total hemolytic complement in the CH50 assay. Subsequently, the C1 fixing ability of a 56 residue fragment derived from the Cμ4 domain of each of these IgM molecules was studied with the C1 fixation assay. One of the three Waldenstrom IgM proteins (Gr) used in the present study was found unable to consume complement in a CH50 assay when tested at the same concentration as the two complement consuming IgM molecules (Dau and Bus). However, when the 56 residue C(H)4 fragment from the Cμ4 domain of each IgM molecule was tested for C1 fixing ability, all three were found to bind C1. On the basis of these observations, it is proposed that a C1 binding site exists within the Cμ4 domain of both complement fixing and noncomplement fixing IgM molecules. Presumably, the latter molecules are unable to interact in their native state with C1 in the manner required for initiation of the classical complement pathway, possibly due to the configurational inaccessibility of the entire C1 binding site.