Dysregulation of TNF signalling has been implicated in a wide variety of inflammatory diseases including rheumatoid arthritis, Crohn’s disease and psoriasis. In most cells, TNF mediates its effects through activation of NF-κB, JNK, p38, and ERK. Here we show that treatment of human monocytic cells with TNF in conjunction with NF-κB inhibition results in an increased expression of Nrf2-regulated genes. Nrf2 has been implicated in conferring protection against many human diseases, including autoimmune diseases, and inflammation. Cytoprotective and detoxification genes including haem oxygenase-1 (HO-1), NADP(H) quinone oxidoreductase (NQO1) and ferritin contain an antioxidant response element (ARE) in their promoter, which is regulated by the transcription factor Nrf2. In this study we showed that TNF treatment plus NF-κB inhibition increased mRNA expression of HO-1, NQO1 and ferritin within 4h in human monocytic cells. Protein expression was observed within 8h of treatment. Nrf2 translocated to the nucleus and bound to the ARE in response to TNF treatment plus NF-κB inhibition. The binding of this complex was inhibited by the addition of Nrf2 supershift antibody. Furthermore, transfection of Nrf2 siRNA significantly inhibited the expression of these genes in response to TNF treatment plus NF-κB inhibition. These results show that treatment with TNF in conjunction with NF-κB inhibition induces the expression of Nrf2 regulated genes in human monocytic cells. Furthermore, they demonstrate a novel TNF signalling mechanism by which Nrf2 may confer protection against certain human disease.