Rift Valley fever virus (RVFV) leads to varied clinical manifestations in animals and in humans that range from moderate fever to fatal illness, suggesting that host immune responses are important determinants of the disease severity. We investigated the immune basis for the extreme susceptibility of MBT/Pas mice that die with mild to acute hepatitis by day 3 post-infection compared to more resistant BALB/cByJ mice that survive up to a week longer. Lower levels of neutrophils observed in the bone marrow and blood of infected MBT/Pas mice are unlikely to be causative of increased RVFV susceptibility as constitutive neutropenia in specific mutant mice did not change survival outcome. However, whereas MBT/Pas mice mounted an earlier inflammatory response accompanied by higher amounts of interferon (IFN)-α in the serum compared to BALB/cByJ mice, they failed to prevent high viral antigen load. Several immunological alterations were uncovered in infected MBT/ Pas mice compared to BALB/cByJ mice, including low levels of leukocytes that expressed type I IFN receptor subunit 1 (IFNAR1) in the blood, spleen and liver, delayed leukocyte activation and decreased percentage of IFN-γ-producing leukocytes in the blood. These observations are consistent with the complex mode of inheritance of RVFV susceptibility in genetic studies. Rift Valley Fever (RVF) is caused by an emerging arbovirus endemic in sub-Saharan African countries. RVF virus (RVFV) may spread as a result of the movement of infected animals. Epizootics are identified by a large number of mass abortions, perinatal mortality and hemorrhagic syndrome in livestock 1. In a minority of infected humans, the disease progresses from a self-limiting febrile illness to severe hepatitis with hemorrhagic manifestations, encephalitis, and ocular lesions 2, 3. The RVFV infection in laboratory rodents mimics many aspects of the pathology in humans 4, 5. In particular, infection of BALB/c mice recapitulates the hepatitis and encephalitis observed in human disease 6. The mouse liver is an early and dominant target of RVFV, with extensive damage to hepatocytes via apoptosis. Mice that survived this early hepatic phase develop infection in the brain. Lymphoid tissues are also affected by RVFV. The main lymphoid lesion is lymphocyte apoptosis (lymphocytolysis) as observed in the thymus, spleen, lymph nodes, and mucosa-associated lymphoid tissues 6, 7. Moreover, a spectrum of pathogenic phenotypes can be observed in inbred mice, as in humans 6, 8–10 , suggesting that host genetic factors are important determinants of the susceptibility to RVF disease. We have previously shown that wild-derived inbred MBT/Pas (MBT) mice are highly susceptible to infection with the virulent RVFV ZH548 and Kenya 98 strains in comparison to more resistant BALB/cByJ (BALB/c) mice 11. We have demonstrated that the susceptibility in MBT mice is a complex trait, inherited in a multifactorial manner 12. Three different quantitative trait loci (QTLs) have been associated with the severity of the disease. The effects of these QTLs are accumulative yet modest, as they explain only 8.3% of the difference in susceptibility between BALB/c and MBT mice. This implies that susceptibility is a result