Purpose: To assess the virologic and immunologic outcome of a treatment simplification strategy based on the substitution of protease inhibitor (PI)-based regimen with abacavir/lamivudine/zidovudine (ABC/3TC/ZDV, also known as trizivir or TZV) plus tenofovir (TDF) in viral-suppressed patients. Method: The study population included 17 HIV-infected patients with undetectable viral loads over 12 months of a stable PI-based therapy. Patients were switched to a combination of TZV (2 pills twice a day) plus TDF (1 pill once a day) and were followed up for 48 months. They were studied for intracellular HIV DNA, CD4 cell count, HIV RNA levels, and lipid metabolism. Results: All patients had undetectable HIV RNA for the entire period of the follow-up. After 24 months of treatment with TZV plus TDF, the levels of cellular HIV DNA significantly decreased (p = .021). When we stratified the patients on the basis of HIV DNA outcome, we observed a significant increase of CD4 count only in patients who had undetectable HIV DNA after 24 months of TZV/TDF treatment. On the contrary, the CD4 count did not change in patients whose HIV DNA was still detectable at 24 months. The percentage of patients taking lipid-lowering agents declined significantly after switching to TZV/TDF. Conclusion: This small pilot study suggests that a single-class quadruple regimen of TZV/TDF may represent a safe and appealing approach in the setting of simplification/switching antiretroviral strategies. © 2007 Thomas Land Publishers, Inc.