Influenza virus has a high mutation rate, such that within a host viral mutations can emerge rapidly. Modelling studies suggest that viral mutations are more likely to emerge in individuals with severe influenza. This may reflect the fact that in severe disease there are often additional rounds of virus replication, which represent additional opportunities for viral mutagenesis. Alternatively, viral variants with mutations that confer reduced fitness (but potentially increased virulence) are able to replicate in immunocompromised individuals and not in individuals with a competent immune response. Obesity is now recognised as one of the leading host co-morbidities that drives the development of severe influenza. Here, we use a mouse model of diet-induced obesity to investigate whether there is increased influenza virus mutagenesis in individuals with obesity. We show that compared to control mice, obese mice infected with A/Auckland/09(H1N1) display increased weight loss, reduced blood oxygen saturation and increased pulmonary virus replication. Obese mice also display pronounced pulmonary inflammation relative to mice fed a low fat diet. Surprisingly, viral deep sequencing showed markedly reduced viral diversity in mice fed a high fat diet. Furthermore, the viral mutations that were so prevalent in mice fed a low fat diet were typically associated with reduced virulence. We therefore propose the following model of disease: The pronounced inflammatory response in obese mice represents a stringent selective pressure such that that only a limited number of viral variants emerge in vivo. However, as the influenza virus strain in question already replicates highly efficiently in mice, the absence of viral mutations ensures that viral replication remains optimal. This enhanced viral replication may then further drive the pro-inflammatory response and contribute to disease severity. Taken together, these data provide the first insight as to the effects of chronic medical conditions on the emergence of viral mutations.