We studied the effect of interferons on the expression of class II histocompatibility (HLA-DR) antigens by cultured adult human astrocytes. Cultures were derived from brain tissue resected for surgical treatment of intractable epilepsy. Cultured astrocytes did not spontaneously display HLA-DR antigen as determined by immunocytochemistry and flow cytometry with antibody to HLA-DR. Astrocytes cultured for 72 h with recombinant or natural interferon-gamma (IFN gamma) demonstrated a dose-dependent increase in HLA-DR expression with optimal stimulation by 100 U/ml IFN gamma. HLA-DR expression was not detectable in astrocytes cultured with IFN gamma for less then 48 h, and peak HLA-DR expression (over 80% of cells) was seen at 120 h of culture. Optimal HLA-DR expression required continuous presence of IFN gamma. Exposure of astrocytes to recombinant or natural interferon-beta (IFN beta) did not induce HLA-DR and pretreatment of astrocytes with IFN beta or interferon-alpha (IFN alpha) significantly inhibited subsequent induction of HLA-DR expression by IFN gamma. These observations suggest that interferons may function in regulating human astrocyte HLA-DR expression within the central nervous system.