Chicken IgY responses against mixtures of six high abundance human plasma proteins were studied across a range of abundances from 1:1 for all six proteins to where one protein predominated above the other five by ≤1000 fold. The ability of any protein in that mixture to mount an IgY response varied. In the 1:1 mixture, human IgG produced the highest and α1antitrypsin the lowest individual responses. However, increasing relative abundance of any protein over others increased the total IgY response (i.e., sum of all responses to each antigen) above those obtained for 1:1 ratios. Increasing relative abundance of any protein over others in the mixture (e.g., 1:10, 1:100 and 1:1000) resulted in variations in response to both the overexpressed antigen and to the other five "constant" proteins. The overriding trends were that as individual proteins became relatively more abundant, they elicited higher IgY responses, while the remaining proteins elicited constant or even decreased responses. This study demonstrates that the ability to mount an IgY response to complex plasma protein antigens (e.g., human plasma) is conclusively driven by a combination of individual antigen immunogenicity and the relative abundance of components within any mixture.