Objectives: To determine the impact of valaciclovir on HIV disease progression in treatment-naive HIV-positive adults. Methods: In this fully blind, multicentre, 1:1 randomized placebo-controlled trial, treatment-naive HIV-1-positive adults with CD4 counts 400–900 cells/mm3 and not meeting contemporaneous recommendations for combination ART (cART) were randomized to valaciclovir 500 mg or placebo twice daily, and followed quarterly until having two consecutive CD4 counts 350 cells/mm3 or initiating cART for any reason. The primary analysis compared the rate of CD4 count decline by study arm after adjusting for baseline CD4 count and viral load (VL). Secondary analyses compared the rate of CD4 percentage decline, HIV VL, herpes simplex virus (HSV) recurrences and drug-related adverse events. The trial closed after release of the START trial results in August 2015. Results: We enrolled 198 participants in Canada, Brazil, Argentina and the UK. Median (IQR) age was 35 (30–43) years. Baseline CD4 count was 592 (491–694) cells/mm3 and VL was 4.04 (3.5–4.5) log10 copies/mL. Over 276 person-years of follow-up, CD4 counts declined by 49 cells/mm3/year in the valaciclovir arm versus 58 cells/mm3/year in the placebo arm (P " 0.65). No differences were seen in the rate of change in CD4 percentage (#1.2%/year versus #1.7%/year, P " 0.34). VL was 0.27 log10 copies/mL lower in valaciclovir participants overall (P,0.001). Placebo participants had more HSV recurrences (62 versus 21/100 person-years, P , 0.0001) but similar rates of grade 2 drug-related adverse events. Conclusions: Unlike prior trials using aciclovir, we found that valaciclovir did not slow CD4 count decline in cARTuntreated adults, although power was limited due to premature study discontinuation. Valaciclovir modestly lowered HIV VL.