HIV protease inhibitors (PIs) have been associated with the serious Metabolic Syndrome, which is the major risk factor of atherosclerotic cardiovascular disease. Atherosclerosis is widely considered to be a chronic inflammatory disease. Macrophages are the most prominent cell type present in atherosclerotic lesions and play essential roles in both early lesion development and late lesion complications. We previously reported that HIV PIs induced accumulation of intracellular free cholesterol and lipids, decreased endoplasmic reticulum (ER) calcium stores, activated the unfolded protein response (UPR), significantly increased apoptosis, and promoted foam cell formation in macrophages. HIV PI-induced ER stress and subsequent activation of the UPR, represents an important cell signaling mechanism of HIV PI-induced metabolic syndromes. Here we show that all HIV PIs, except amprenavir, increased expression of the major mediators of inflammatory response, TNF-alpha and IL-6, to varying degrees. Furthermore, we show that the RNA-binding protein, HuR, plays an important role in HIV PI-induced expression of TNF-alpha and IL-6. Atazanavir increased the cytoplasmic levels of HuR and enhanced the binding of HuR to 3'-UTR of TNF-alpha and IL-6. Down regulation of HuR expression by siRNA prevented atazanavir-induced increase of TNF-alpha and IL-6. These results suggest that HuR might have an impact on pathophysiological processes of HIV PI-induced atherosclerosis.