Mice have close genetic/physiological relationships to humans, breed rapidly and can be genetically modified, making them the most-used mammal in biomedical research. As the sole gas transporter in vertebrates, diseases of the red blood cell (RBC) are frequently severe; much research has therefore focused on RBC and cardiovascular disorders of mouse and humans. RBCs also host malaria parasites. Recently, we presented an in-depth proteome for the human RBC. Here, we present directly comparable data for the mouse RBC as membrane-only, soluble-only and combined membrane-bound/soluble proteomes (comprising respectively 247, 232 and 165 proteins). All proteins were identified, validated and categorized in terms of sub-cellular localization, protein family and function and, in comparison with the human RBC, were classified as orthologs, family-related or unique. Splice isoforms were identified and polypeptides migrating with anomalous apparent molecular weights were grouped into putatively ubiquitinylated or partially degraded complexes. Overall there was close concordance between mouse and human proteomes, confirming the unexpected RBC complexity. Several novel findings in the human proteome have been confirmed here. This comparison sheds light on several open issues in RBC biology and provides a departure point for more comprehensive understanding of RBC function.