BACKGROUND High rates of virologic failure have been reported in antiretroviral-naive patients receiving triple-nucleoside reverse transcriptase inhibitor (NRTI) combinations containing tenofovir disoproxil fumarate (TDF) with lamivudine (3TC) and didanosine or 3TC and abacavir (ABC). A regimen of once-daily zidovudine (ZDV), 3TC, ABC, and TDF showed an acceptable virologic success rate, however. METHODS This was a pilot prospective cohort study. Treatment-naive subjects were offered a fixed-dose combination of ZDV/3TC (300 mg/150 mg) twice daily and 300 mg of TDF once daily. RESULTS Fifty-one patients were enrolled between April 2002 and March 2005. At baseline, the median CD4 count was 230 cells/microL (range: 23-425 cells/microL), 20 (39%) of 51 subjects had CD4 counts of < 200 cells/microL, the median HIV-1 viral load was 4.89 log (3.14 to >5.87 log), and 24 (47%) of 51 subjects had a viral load >5 log. The median follow-up was 12 months (range: 1 week to 38 months). On-treatment analysis showed a median HIV RNA load decrease of -1.7 log after 1 to 2 weeks of treatment and -2.41 log after 1 month, and 34 (89%) of 38 subjects had a viral load < 50 copies/mL at month 6, 21 (78%) of 27 at month 12, and 13 (81%) of 16 after 18 months (intent-to-treat results were 34 [72%] of 47 subjects, 21 [56%] of 36 subjects, and 13 [50%] of 25 subjects at months 6, 12, and 18, respectively). The median CD4 count increase at month 18 was 142 cells/microL. Nine (17.6%) of 51 treatment interruptions for adverse effects were seen. Six viral failures occurred, including 2 with K65R mutations (alone or associated with Y115F and M184V). CONCLUSIONS The combination of ZDV/3TC + TDF in treatment-naive HIV-infected subjects induces a rapid and sustained HIV-1 RNA decrease and is associated with a good immunologic response. No severe adverse events occurred. This triple-NRTI combination needs to be evaluated further.