Removal of just the three N-terminal residues Lys-Val-Phe (TIP) on hen egg white lysozyme (HEL), by aminopeptidase cleavage, eliminates an antigenic determinant which is a recurrent and dominant focus of primary but not secondary antibody responses to HEL in a variety of mouse strains. We have generated an anti-idiotypic rabbit antiserum against such a TIP-dependent monoclonal antibody (mAb). This antiserum reacts with many different primary anti-HEL mAb, but fails to react with all of a variety of secondary anti-HEL mAb. The idiotype defined by this antiserum, termed IdXE, is a common feature of early anti-HEL antibody responses but does not appear in secondary responses. Although the presence of IdXE and TIP dependence is correlated in primary responses, studies of idiotype expression on mAb and on plaque-forming cells (PFC) using mixed erythrocyte monolayers clearly show that at the single-cell level the properties are separable, i.e., not all TIP-recognizing PFC display IdXE and a sizable proportion of cells producing non-TIP-dependent antibodies are IdXE+. The restricted idiotypy and specificity of early antibody responses to HEL occur in each of eight diverse mouse strains tested: it is not associated with a particular MHC haplotype, heavy chain allotype or light chain allotype. The finding of such strain-independent restriction in the early response pattern to a typical protein antigen is novel and suggests the involvement of highly conserved, potent regulatory mechanisms which are manifested as a limitation in the initial expression of the available repertoire.