Arenaviruses are usually rodent-borne viruses that constitute a major threat for human health. Among them, Lassa Fever Virus (LFV) occurs in Western Africa where it infects hundreds of thousands of people annually. According to the most recent surveys, LFV is hosted by one of the multimammate rats, Mastomys natalensis, but has never been detected in its sibling and sometimes sympatric species Mastomys erythroleucus. This pattern suggests that intrinsic, i.e. genetic properties underlie such a drastic epidemiological difference (M. natalensis as a reservoir vs. M. erythroleucus as a non-reservoir species). Here we investigate genomic differences between these two closely related rodent species by focusing on three genes that have recently been described as pivotal for LFV/human cell interactions: Dystroglycan (the LFV cellular receptor). LARGE-1 and LARGE-2 (two enzymes that are essential to Dystroglycan functioning). For all three genes, sequence analyses showed that amino-acid chains undergo extremely strong purifying selective pressures, and indicated that no nucleotide (therefore no tertiary structure) change can be advocated to explain species-specific differences in LFV-cellular mediation. Nevertheless, preliminary studies of kidney-specific expression profiles suggested that important species-specific differences exist between Mastomys species. Taking into account current knowledge about LFV-human cell interactions, our results may point towards a possible role for LARGE-1 and LARGE-2 enzymes at the intracellular replication level of the virus, rather than at the LFV-host cell receptor binding step.