HIV-associated nephropathy is caused, in part, by direct infection of kidney epithelial cells by HIV-1. In the spectrum of pathogenic host-virus interactions, abnormal activation or suppression of host transcription factors is common. NF-B is a necessary host transcription factor for HIV-1 gene expression, and it has been shown that NF-B activity is dysregulated in many naturally infected cell types. We show here that renal glomerular epithelial cells (podocytes) expressing the HIV-1 genome, similar to infected immune cells, also have a dysregulated and persistent activation of NF-B. Although podocytes produce p50, p52, RelA, RelB, and c-Rel; electrophoretic mobility shift assays and immunocytochemistry showed a predominant nuclear accumulation of p50/RelA-containing NF-B dimers in HIV-1 expressing podocytes as compared to normal. In addition, the expression level of a transfected NF-B reporter plasmid was significantly higher in HIVAN podocytes. The mechanism of NF-B activation involved increased phosphorylation of IB, resulting in an enhanced turnover of the IB protein. There was no evidence for regulation by IB or the alternate pathway of NF- B activation. Altered activation of this key host transcription factor likely plays a role in the well described cellular phenotypic changes observed in HIVAN such as proliferation. Studies with inhibitors of proliferation and NF-B suggest that NF-B activation may contribute to the proliferative mechanism in HIVAN. In addition, since NF-B regulates many aspects of inflammation, this dysregulation may also contribute to disease severity and progression through regulation of pro-inflammatory processes in the kidney microenvironment.