Objective. To determine whether antibodies against high-density lipoprotein (aHDL) and apolipoprotein A-I (aApo A-I) interfere with the anti-atherogenic functions of high-density lipoprotein (HDL) and relate to disease activity and damage in SLE. Methods. Seventy-seven SLE patients were compared with an age-and sex-frequency matched control group. Immunoglobulin G (IgG) aHDL, IgG aApoA-I, soluble vascular cell and intracellular cell adhesion molecules (VCAM-1 and ICAM-1, respectively) were measured by ELISA, paraoxonase (PON) activity by spectrophotometry, nitric oxide (NOx) metabolites by the Griess reaction, and total anti-oxidant capacity (TAC) by chemiluminescence. Results. Compared with controls, SLE patients showed higher titres of IgG aHDL (P < 0.0001) and IgG aApo A-I (P < 0.0001), lower PON activity (P < 0.0001), increased NOx (P < 0.0001), VCAM-1 (P < 0.0001) and ICAM-1 (P = 0.0008) and lower TAC (P = 0.0006). Titres of IgG aHDL positively correlated with IgG aApo A-I (r = 0.64, P < 0.0001), NOx (r = 0.32, P = 0.007), inversely correlated with PON activity (r = -0.34, P = 0.002) and TAC (r = -0.43, P = 0.0004) and were independently associated with ICAM-1 (t = 3.509, P = 0.001). IgG aApo A-I titres correlated positively with NO (r = 0.37, P = 0.007), inversely with PON activity (r = -0.31, P = 0.006), TAC (r = -0.47, P < 0.0001) and were independently associated with HDL (t = -2.747, P = 0.008) and VCAM-1 (t = 3.311, P = 0.002), the latter alongside NOx (T = 2.271, P = 0.02). Elevated titres of IgG aHDL and IgG aApo A-I and reduced PON activity related to increased disease score (BILAG) and damage index (SLICC/ACR DI). Conclusion. In SLE, IgG aHDL and aApo A-I associate with disease activity and damage and interfere with the anti-oxidant and anti-inflammatory functions of HDL favouring atherogenesis.