The ongoing coronavirus disease-2019 (COVID-19) pandemic, caused by a novel coronavirus termed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that is closely related to SARS-CoV, poses a grave threat to global health and has devastated societies worldwide. One puzzling aspect of COVID-19 is the impressive variation in disease manifestations among infected individuals, from a majority who are asymptomatic or exhibit mild symptoms to a smaller, largely age-dependent fraction who develop life-threatening conditions. Some of these differences are likely the consequence of host genetic factors. Systems genetics using diverse and replicable cohorts of isogenic mice represents a powerful way to dissect those host genetic differences that modulate microbial infections. Here we report that the two founders of the large BXD family of mice-C57BL/6J and DBA/2J, differ substantially in their susceptibility to a mouse-adapted SARS-CoV, MA15. Following intranasal viral challenge, DBA/2J develops a more severe disease than C57BL/6J as evidenced by more pronounced and sustained weight loss. Disease was accompanied by high levels of pulmonary viral replication in both strains early after infection but substantially delayed viral clearance in DBA/2J. Our data reveal that the parents of the BXD family are segregated by clear phenotypic differences during MA15 infection and support the feasibility of using this family to systemically dissect the complex virus-host interactions that modulate disease progression and outcome of infection with SARS-CoV, and provisionally also with SARS-CoV-2.