Endotoxin tolerance has been described in bacterial lipopolysaccharides (LPS) pretreated macrophages as the diminished release of proinflammatory cytokines on a subsequent challenge with LPS. The transcription factor complex hypoxia inducible factor-1 (HIF-1) known as the key regulator of hypoxia induced gene expression was shown to play an important integrative role in conditions of hypoxia and inflammation. LPS as well as proinflammatory cytokines induce HIF-1 in a non hypoxic manner. In the human monocytic cell line THP-1 acute LPS treatment induced HIF-1α accumulation and expression of HIF target genes as well as the release of inflammatory cytokines. Cells made tolerant by pretreatment with LPS showed diminished expression and release of inflammatory cytokines after an acute LPS stimulation. Moreover, HIF-1α protein levels after hypoxic stimulation were diminished in LPS-tolerant cells and LPS-induced HIF-1a gene expression was significantly reduced. The expression of the HIF-1 target gene adrenomedullin (ADM) after hypoxic and LPS stimulation was likewise lower in LPS-tolerant cells. From these results we conclude that LPS inducible HIF-1α accumulation shows typical features of classical endotoxin tolerance. This tolerance may contribute to changes of hypoxic responses in leukocytes during inflammation.