Since CD200 is involved in many diseases and its splice variant CD200 tr is an antagonist to CD200, identification of the mechanism controlling the relative expression levels of CD200 versus CD200 tr may provide insight into novel strategies for treatment of clinical disorders. In the present study, we have explored the mechanism controlling CD200 alternative splicing and show that SF2/ASF regulates CD200 alternative splicing through its direct binding to an ESE site in exon 2 of this gene. The level of SF2/ASF determines the alternative splicing patterns in different tissues or cells. Interestingly, in a mouse model of viral infection, we detected for the first time that the normal splicing pattern of CD200 was reversed in the lung tissue of A/J mice infected with mouse hepatitis virus strain I (MHV-1), following an increase in expression of SF2/ASF in this MHV-1 susceptible mouse strain.