Background: Ascariasis is a neglected tropical disease that affects 800 million people worldwide. Whereas most people only experience light worm burden, some people experience heavy worm burdens even after several rounds of chemotherapy, a phenomenon known as predisposition. Such heavy infections are associated with more severe symptoms and increased chronic morbidity. Methods: In order to investigate potential mechanisms that may explain the observed predisposition, we infected mice with the porcine ascarid Ascaris suum using an established mouse model with two different mouse strains, where the C57BL/6J strain is more susceptible to infection and therefore a model for heavy infection and the CBA/Ca strain is more resistant and thus a model for light infection. At day 7 post-infection we investigated the liver proteome, using shotgun mass spectrometry, of both infected and control mice of each strain. Results: We identified intrinsic differences, between the two mouse strains, in both oxidative phosphorylation proteins and proteins involved in retinol metabolism. Additionally, we found differences between the two mouse strains in activation of the complement system, where the CBA/Ca strain has higher protein abundances for lectin pathway proteins and the C57BL/6J strain has higher protein abundances for complement inhibiting proteins. The CBA/Ca strain had a higher abundance of proteins involved in the activation of the complement cascade via the lectin pathway. In contrast, the C57BL/6J strain demonstrated a higher abundance of proteins involved in arresting the complement pathway. Conclusions: We observed clear differences between the two mouse strains both intrinsically and under infection.