CD40 is a type I membrane-bound molecule belonging to the TNFR superfamily that is expressed on various immune cells including macrophages and microglia. The aberrant expression of CD40 is involved in the initiation and maintenance of various human diseases including multiple sclerosis, arthritis, atherosclerosis, and Alzheimer's disease. Inhibition of CD40 signaling has been shown to provide a significant beneficial effect in a number of animal models of human diseases including the aforementioned examples. We have previously shown that IFN-γ induces CD40 expression in macrophages and microglia. IFN-γ leads to STAT-1α activation directly and up-regulation of NF-κB activity due to the secretion and subsequent autocrine signaling of TNF-α. However, TNF-α alone is not capable of inducing CD40 expression in these cells. Suppressor of cytokine signaling 1 protein (SOCS-1) is a cytokine-inducible Src homology 2-containing protein that regulates cytokine receptor signaling by inhibiting STAT-1α activation via a specific interaction with activated Janus kinase 2. Given the important role of CD40 in inflammatory events in the CNS as well as other organ systems, it is imperative to understand the molecular mechanisms contributing to both CD40 induction and repression. We show that ectopic expression of SOCS-1 abrogates IFN-γ-induced CD40 protein expression, mRNA levels, and promoter activity. Additionally, IFN-γ-induced TNF-α secretion, as well as STAT-1α and NF-κB activation, are inhibited in the presence of SOCS-1. We conclude that SOCS-1 inhibits cytokine-induced CD40 expression by blocking IFN-γ-mediated STAT-1α activation, which also then results in suppression of IFN-γ-induced TNF-α secretion and subsequent NF-κB activation.