We have used RNA differential display to identify specific mRNA species that are regulated by interferon-γ (IFNγ) treatment of enriched astrocyte cultures. Following a 24-hour treatment with IFN, mRNA was subjected to differential display using 15 different random primers. 105 upregulated and 5 downregulated cDNAs were selected for further sequencing and identification. Northern blot analysis confirmed the upregulation of 13 genes identical or highly similar to: intercrine, adrenomedullin, H-revl07, CAP-like protein, ATP synthase Ε-subunit, complement C3, S-100β, Ca<sup>2+</sup> ATPase, mgl1, IFN-upregulated 56-kD protein mRNA, laminin receptor-like protein, protein tyrosine phosphatase, and zic. These data suggest that exposure to IFNγ results in a complex change in the pattern of astrocyte gene expression.