Potential mechanisms underlying the strong increase in CD16⁺⁺M-DC8⁺ monocytes that might be a therapeutic target to fight TNFα-mediated chronic inflammation during HIV infection. Chronic immune activation drives the progression of HIV infection and is thought to be one of the prediction parameters of disease outcome. As in Crohn disease, systemic LPS translocation and TNFα overproduction seem to play a major role in this activation. However, the cellular origins of this TNFα overproduction have remained elusive. We demonstrate here that in the blood from viremic patients, CD16⁺⁺M-DC8⁺ monocytes are found in higher numbers than in virologically suppressed patients, and that they account for a large part of the TNFα overproduction in response to LPS. The potential mechanisms underlying this increase in proinflammatory CD16⁺⁺M-DC8⁺ monocytes may be a defective migration into tissues, a high level of recirculation between organs, a specific proliferation or resistance to apoptosis, or a greater differentiation from another myeloid cell subset. In line with this hypothesis, we show that CD16⁺⁺M-DC8⁺ monocytes can arise in vitro from CD14⁺⁺CD16⁻ classical monocytes in the presence of GM-CSF and M-CSF, and high GM-CSF and TNFα levels, as well as high levels of sCD14, an indicator of LPS translocation, are indeed found in the plasma from viremic patients with high numbers of M-DC8⁺ monocytes.