The idiotypic cross-reactivity of mouse and human monoclonal immunoglobulins with binding activity for phosphorylcholine (PC) was investigated, using an idiotypic antibody elicited against the PC-binding human IgMFR. The isolated FR heavy chain proved to be a better inhibitor for the reaction of IgMFR with anti-FR than the FR light chain, but the intact protein was necessary for full idiotypic expression. PC was an inhibitor only at concentrations greater than 10(-3) M indicating that the idiotypic antibody was not combining site-directed. Among the murine PC-binding IgA myeloma proteins, MOPC 167 was found to be the best inhibitor, but its inhibitory capacity was about 4 orders of magnitude lower than that of the homologous IgMFR. McPC 603 was an even weaker inhibitor, while TEPC 15 effected no better inhibition than human monoclonal immunoglobulins without PC-binding activity. MOPC 167 has a most similar binding specificity to IgMFR as indicated by the high affinity for choline of these two proteins. TEPC 15 and McPC 603, on the other hand, exhibit a much lower affinity for choline. In addition to their similarity in specificity, proteins FR and MOPC 167 show important structural similarities within parts of their heavy and light chain variable domains. The data provide some evidence for the existence of idiotypic cross-reactivity between the two species man and mouse.