A role of the nuclear receptor Rev-erb in the regulation of transcription pathways involving other nuclear receptors is emerging. Indeed, Rev-erb is a negative regulator of transcription by binding to overlapping response elements shared with various nuclear receptors, including the peroxisome proliferator-activated receptors (PPARs) and the retinoid-related orphan receptor alpha (ROR). Here, we show that Rev-erb is expressed in primary human macrophages and that its expression is induced by synthetic ligands for the liver X receptors (LXRs), which control cholesterol homeostasis, inflammation and the immune response in macrophages. LXR binds to a specific response element in the human Rev-erb promoter thus inducing Rev-erb transcriptional expression. Interestingly, Rev-erb does not influence basal or LXR-regulated cholesterol homeostasis. However, Rev-erb over-expression represses the induction of toll like receptor (TLR)-4 by LXR agonists, whereas Rev-erb silencing by siRNA results in enhanced TLR-4 expression upon LXR activation. Electrophoretic mobility shift, chromatin immunoprecipitation (ChIP) and transient transfection experiments demonstrate that Rev-erb represses human TLR-4 promoter activity by binding as a monomer to a RevRE site overlapping with the LXRE site in the TLR-4 promoter. These data identify Rev-erb as a new LXR target gene, inhibiting LXR-induction of TLR-4 in a negative transcriptional feedback loop, but not cholesterol homeostasis gene expression.