Affinity selections by phage display or other display techniques are typically performed against single targets immobilized as a purified protein. In order to develop cross-specific binders that engage with multiple proteins, such as members of a related family, we herein propose to perform selections against mixtures of proteins as bait. Combined with follow-up selection rounds against the individual proteins, deep sequencing, and single clone enrichment analysis, we expected to distinguish binders that are cross-specific from those that are not. Indeed, applying the strategy to human and mouse coagulation factor XI (hFXI and mFXI), and thus to a situation with limited complexity due to a mixture of only two targets, allowed rapid identification of peptide-based binders along with precise information about their specificity. The study also provided insights into the dynamics and challenges of multitarget affinity selections, showing that one target can easily dominate the selection process and hinder the enrichment of binders to other proteins in a mixture.