OBJECTIVES To determine the existence of autoantibodies against apolipoprotein A-1 (anti-apoA-1 IgG) in HIV patients and explore their association with biological features of HIV infection and different inflammatory biomarkers. We also evaluated their impact on CD4 lymphocytes survival. METHODS Anti-apoA-1 IgG plasma levels were assessed by ELISA in 237 HIV positive patients from a national prospective cohort with no current lipid-lowering therapy. RESULTS 58% of patients were found positive for anti-apoA-1 IgG and were associated with lower CD4 counts, but higher viremia and systemic inflammation. Logistic regression analyses indicated that high anti-apoA-1 IgG levels were associated with a 16-fold increased risk of displaying low CD4 levels, independent of HIV RNA levels and treatment (adjusted Odds ratio [OR]:16.1, 95% Confidence Interval [95%CI]:1.80-143.6; p = 0.01), and a 6-fold increased risk of having a detectable viremia, independent of antiretroviral treatment (OR:5.47; 95% CI:1.63-18.36; p = 0.006). In vitro, anti-apoA-1 IgG induced dose and time-dependent CD4 apoptosis that was increased by exposure to HIV RNA. CONCLUSIONS In HIV patients, anti-apoA-1 IgG levels are associated with low CD4+ counts, high viremia and a pro-inflammatory systemic profile. Anti-apoA-1 IgG can promote CD4+ lymphocyte apoptosis via undefined pathways.