Gamma interferon-inducible lysosomal thiol reductase (GILT) is an enzyme that catalyzes thiol bond reduction and plays an important role in the early steps of antigen processing. The key factor involved in the regulation of GILT expression upon cell stimulation with interferon-γ (IFN-γ) is signal transducer and activator of transcription 1 (STAT1). In this study, we examined the role of STAT1 in regulating the constitutive expression of GILT. We showed that STAT1 interacts with the GILT promoter, even in the absence of IFN-γ, and that STAT1 represses GILT expression. These results reveal an atypical negative regulatory role for STAT1 in the constitutive regulation of genes involved in antigen processing.