As immune responses in the CNS are highly regulated, cell-specific differences in IFNgamma signaling may be integral in dictating the outcome of host cell responses. In comparing the response of IFNgamma-treated primary neurons to control MEF, we observed that neurons demonstrated lower basal expression of both STAT1 and STAT3, the primary signal transducers responsible for IFNgamma signaling. Following IFNgamma treatment of these cell populations, we noted muted and delayed STAT1 phosphorylation, no detectable STAT3 phosphorylation, and a 3-10-fold lower level of representative IFNgamma-responsive gene transcripts. Moreover, in response to a brief pulse of IFNgamma, a steady increase in STAT1 phosphorylation and IFNgamma gene expression over 48 h was observed in neurons, as compared to rapid attenuation in MEF. These distinct response kinetics in IFNgamma-stimulated neurons may reflect modifications in the IFNgamma negative feedback loop, which may provide a mechanism for the cell-specific heterogeneity of responses to IFNgamma.