Background: Due to superior long-term toxicity profile, AZT and TDF are preferred to d4T for first-line regimens. However, short-term d4T use could be beneficial in avoiding AZT-induced anemia. Method: Naive Thai HIV-infected adults were randomized (1:1:1) to arm 1: 24-wk d4T 30 mg + 3TC 150 mg + NVP 200 mg followed by 48-wk AZT 250 mg + 3TC 150 mg + NVP 200 mg; arm 2: 72-wk AZT 250 mg + 3TC 150 mg + NVP 200 mg; or arm 3: 72-wk TDF 300 mg + FTC 200 mg + NVP. During NVP lead-in, AZT was given at 200 mg or 300 mg BID for weight <60 kg or >60 kg, respectively. Hemoglobin, DEXA, neuropathic signs, serum creatinine, CD4 count, plasma HIVRNA, and adherence were assessed. Results: Among 150 randomized patients, 55% were female, mean (SD) age was 34 (8) years. Baseline mean CD4 count was 161 (94) cells/mm3 , HIV-RNA was log10 4.87 (0.65) copies/ml, hemoglobin was 12.5 (1.6) g/dL, weight was 57.9 (10.8) kg, and eGFR (MDRD formula) was 82.9 (15.5) mL/min/1.73m2 . CD4 count increased more in arm 1 than arm 2 and arm 3 from baseline to week 24 (168 vs. 117 and 118 cells/mm3 , p=0.01 and 0.02, respectively) but the increase from baseline to week 72 was similar among arms. At week 72, HIV-RNA was <40 copies/mL in 84%, 92%, and 83% of patients in arms 1, 2, and 3, respectively. Adherence was similar between arms. At week 24, mean hemoglobin decreased significantly from baseline in arm 2 compared to arm 1 (-0.19 vs. 0.68 g/dL, p=0.001) and arm 3 (0.48 g/dL, p=0.010), and neuropathic signs were significantly more common in arm 2 compared to arm 3 (20.4% vs. 4.2%, p=0.028). 2 There were no differences in changes in peripheral fat and eGFR from baseline between arms. At week 72, mean hemoglobin in arm 3 significantly increased from baseline compared to arm 1 (0.90 vs. 0.17 g/dL, p=0.006). Arm 1 had larger decrease in peripheral fat (-301 g) from baseline than arm 2 (143 g) and arm 3 (281 g) but this did not reach statistically significant level. Only 1 patient in arm 2 had clinical lipoatrophy. Proportion of patients with neuropathic signs or changes in eGFR from baseline were not different between arms. Conclusions: Short-term d4T use before introducing AZT caused less anemia and peripheral neuropathic signs compared to initiating treatment with AZT. Initial rise in CD4 count was greatest with d4T. However, peripheral fat reduction by DEXA could be observed at 1 year after d4T discontinuation but this was not observed clinically. A 6-month d4T lead-in therapy could be considered in patients with anemia or low baseline CD4 count. This study provides information to guide global ARV initiation recommendations where AZT is more commonly used than TDF in first-line regimens.