Background: The aim of this study was to assess changes in the size and cholesterol content of low-density lipoproteins (LDL) and changes in lipoprotein-associated phospholipase A2 (Lp-PLA2) activity in HIV-infected patients switching to tenofovir + emtricitabine (TDF+FTC) or abacavir + lamivudine (ABC+3TC). Methods: This was a substudy of a multicentre randomized trial comparing TDF+FTC with ABC+3TC-based regimens in patients with virological suppression. Fasting lipids and apolipoproteins (apo), LDL size and cholesterol content and Lp-PLA2 activity were measured at baseline and at week 48. Results: A total of 62 patients, naive for the compared drugs, were included. At baseline, groups were comparable except for total Lp-PLA2 activity (P=0.047) and for a tendency towards the use of a major baseline thymidine analogue in the TDF+FTC arm (25 versus 18 patients; P=0.054). In the ABC+3TC arm a significant increase in total cholesterol (0.64 mmol/l; P=0.003), high-density lipoprotein cholesterol (HDL-c, 0.13 mmol/l; P=0.031), triglycerides (0.39 mmol/l; P=0.036), apo A-I (0.12 g/l; P=0.006), apo B (0.16 g/l; P=0.015) and non-HDL-c (0.50 mmol/l; P=0.009) concentrations was observed at week 48 compared with the TDF+FTC treatment arm. In addition, an increase in the cholesterol content of small, dense LDL subfractions (0.48 mmol/l; P=0.003) and a decrease in LDL size (-2.6 nm; P=0.011) was observed in the ABC arm without changes in the TDF patients. Total PLA2, LDLPLA2 and HDL-PLA2 activity decreased in the TDF arm, but multivariate analysis showed baseline PLA2 values and previous use of thymidine analogues as the factors associated with these changes. Estimated cardiovascular risk did not change in either arm. Conclusions: A more atherogenic LDL profile, including a decrease in LDL size, was found in the ABC group and not in TDF patients.