HIV protease inhibitors are important pharmacological agents used in the treatment of HIV infected patients. One of the major disadvantages of HIV protease inhibitors is that they increase several cardiovascular risk factors including the expression of CD36 in macrophages. The expression of CD36 in macrophages promotes the accumulation of cholesterol, the development of foam cells, and ultimately atherosclerosis. Recent studies have suggested that -tocopherol can prevent HIV protease inhibitor-induced increases in macrophage CD36 levels. Because of the potential clinical utility of using -tocopherol to limit some of the side-effects of HIV protease inhibitors, we tested the ability of -tocopherol to prevent ritonavir, a common HIV protease inhibitor, from inducing atherosclerosis in the LDLR mouse model. Surprisingly, -tocopherol did not prevent ritonavir-induced atherosclerosis. However, co-treatment with the nucleoside reverse transcriptase inhibitors (NRTIs), didanosine or D4T, did prevent ritonavir-induced atherosclerosis. Using macrophages isolated from LDLR mice we demonstrated that the NRTIs prevented the up-regulation of CD36 and cholesterol accumulation in macrophages. Treatment of LDLR mice with NRTIs promoted the ubiquitination and down-regulation of protein kinase C (PKC). Previous studies demonstrated that HIV protease inhibitor activation of PKC was necessary for the up-regulation of CD36. Importantly, the in vivo inhibition of PKC with chelerythrine prevented ritonavir-induced up-regulation of CD36, accumulation of cholesterol, and the formation of atherosclerotic lesions. These novel mechanistic studies suggest that NRTIs may provide protection from one of the negative side effects associated with HIV protease inhibitors, namely the increase in CD36 levels and subsequent cholesterol accumulation and atherogenesis.