Binding of human 125I-C-reactive protein (CRP) to sheep erythrocytes sensitized with pneumococcal C polysaccharide (E-PnC) was found to be Ca++-dependent and inhibitable by phosphocholine, CRP, and HOPC 8. Binding of 125I-HOPC 8 to E-PnC was Ca++-independent but could also be inhibited by phosphocholine, CRP, and HOPC 8. Thus, CRP and HOPC 8, despite a differential Ca++ requirement, share a common binding specificity for phosphocholine. A monoclonal anti-idiotypic antibody (MAB), GB4-10, prepared in A/J mice immunized with BALB/c HOPC 8 inhibited the binding of both 125I-HOPC 8 to E-PnC. In addition, both proteins bound to GB4-10 immobilized on polysterene tubes. Interestingly, binding of 125I-CRP to GB4-10 required Ca++. Similar results were also obtained with another MAB (AB1-2) prepared similarly to GB4-10, whereas neither protein bound to a control MAB (EB3-7) against an α1→3 dextran-binding myeloma protein, J558. Binding of 125I-HOPC 8 to GB4-10 could be inhibited by HOPC 8, keykole limpet hemocyanin-phosphocholine but not phosphocholine, and in the presence of Ca++ by CRP. These data indicate that CRP bears antigenic determinants cross-reacting with certain idiotype determinants on HOPC 8. They also suggest that Ca++ acts as an allosteric effector, perhaps stabilizing the phosphocholine-binding site of CRP.