Red blood cells (RBC) play a critical role in oxygen transport, and are the focus of important human diseases including malaria and the haemoglobinopathies. Although previous studies aimed at classifying the RBC proteome have examined whole or membrane-enriched fractions from RBC, none have used specific strategies directed at enriching proteins with exposed extracellular domains. Furthermore, there has been no systematic analysis of variation in abundance of RBC surface proteins either within or between genetically disparate human populations. These questions are of particular importance to inform not only basic RBC biology but additionally to identify novel candidate Plasmodium receptors, where selective pressures have moulded the RBC surface, exemplified by genetic absence of Duffy antigen in populations from sub-Saharan Africa. Here, we use ‘Plasma membrane profiling’ and tandem mass tag-based mass spectrometry to specifically enrich and quantify cell surface proteins from primary RBC from two sets of nine donors from the UK or Senegal. We define a ‘stringent’ and ‘sensitive’ RBC surface proteome and identify potential candidate Plasmodium receptors on the basis either of diminished protein abundance, or increased variation in West African individuals compared to people from the UK.