We report here the novel finding that HIV-negative factor (Nef) protein is present in considerable numbers of peripheral blood mononuclear cells (PBMCs) from viremic HIV-infected patients not on antiretroviral therapy (ART) and also in patients receiving virologically suppressive ART, though to a smaller degree. Interestingly, these Nef-positive PBMCs constitute predominantly uninfected bystander cells. These results may explain systemic pathology in HIV patients, even in those receiving ART.