The immune system of a healthy individual responds vigorously to foreign microbial antigens. However, all potentially immunogenic regions (determinants) within an antigen are not functionally of equal relevance in mediating host immunity against the pathogen. Moreover, some of these antigenic determinants are well processed and presented (immunodominant), while others are not revealed (cryptic) from the native antigen. Nevertheless, cryptic determinants are good immunogens in the pre-processed peptide form. Defining the factors influencing the dominance versus the crypticity of antigenic determinants is critical to advancing our understanding of the individual variations in host immunity to infection, autoantigens and vaccination. In this study based on a model antigen, hen eggwhite lysozyme (HEL), we describe that the major histocompatibility complex (MHC) haplotypes imprint and the non-MHC genes modify the dominance versus the crypticity of a specific antigenic determinant. Both the H-2q- and the H-2d-bearing mice raised potent response to native HEL, but responded differently to its determinant region 57–78, which was dominant in the H-2q but cryptic in the H-2d mice. The H-2q- but not the H-2d-bearing mice of three different genetic backgrounds yielded patterns of graded reactivity to epitope 57–78 showing the fine-tuning effect of the non-MHC genes. Interestingly, the F1 (H-2q × H-2d) mice retained the dominant response profile of the H-2q parent regardless of the contributing gender, and also responded to a new sub-determinant 61–75. These results highlight the genetic factors influencing the dominance/crypticity of a specific antigenic determinant.