Background: Abacavir use has been associated with cardiovascular disease (CVD) risk, but this effect has not been consistent across studies. Methods: To explore abacavir-related CVD risk we studied 27 HIV-positive participants taking fixed-dose abacavir/ lamivudine-based antiretroviral therapy (ART) with viral suppression and randomized them to remain on their current regimen (n=13) or switch the nucleoside component to tenofovir disoproxil fumarate (DF)/emtricitabine (n=14). Plasma biomarkers were measured at baseline and at 1 and 6 months. Results: At baseline, median (IQR) age was 46 years (41-53) and CD4+ count 620 cells/mm3 (477-836). There were no baseline differences in individual CVD risk factors between groups, however, 10-year Framingham Risk Score (FRS) trended higher for those taking abacavir (8.5%) versus tenofovir DF (4.7%). Switching to a tenofovir DF-based ART regimen, compared with staying on abacavir-based ART, was associated with a 79% lower level of high sensitivity C-reactive protein (hsCRP; p=0.04) and a 52% lower inflammatory/coagulation rank composite (consisting of hsCRP, interleukin-6 and D-dimer levels).These findings were not attenuated after adjusting for 10-year FRS (-79% for hsCRP, p=0.06; -50% for inflammatory composite, p=0.003). Conclusion: Larger, prospective, randomized studies are needed to verify whether switching from abacavir/ lamivudine- to tenofovir DF/emtricitabine-based ART, in the context of viral suppression, reduces inflammation and corresponding CVD risk.