IMPORTANCE Coronaviruses cause diseases with various degrees of severity in humans, including severe acute respiratory syndrome (SARS). In domestic and companion animals, coronaviruses induce interferon (IFN) in only a few cell types. In particular, macrophages, which are known to have both protective and pathogenic roles in coronavirus infections, express IFN while dendritic cells do not. Little is known about the basis of these cell-specific differences in IFN induction. Here, we show that an animal coronavirus, mouse hepatitis virus, induces IFN and other IFN-responsive molecules in macrophages, but not in dendritic cells, via a feedback loop that is dependent upon low-level IFN expression at early times after infection. This pathway of cellular activation may be a useful target for modulating macrophage function in order to selectively enhance the antivirus immune response and diminish the pathogenic role of these cells in SARS and other coronavirus infections.