Background Whether integrase strand transfer inhibitors (INSTIs) can decrease HIV-1 DNA levels more rapidly than boosted PIs during primary HIV-1 infection (PHI) is unknown. We hypothesized that once-daily dolutegravir/tenofovir/emtricitabine could reduce the viral reservoir through rapid viral replication control further than once-daily darunavir/cobicistat/tenofovir/emtricitabine. Methods The OPTIPRIM2-ANRS 169 study was a randomized (1:1), open-label, multicentre trial in adults with ≤q5 or ≤q3 HIV antibodies detected, respectively, by western blot or immunoblot in the last 10\hspace0.25emdays. The primary endpoint was total HIV-1 DNA levels in PBMCs at Week 48 (W48) adjusted for baseline levels. The main secondary endpoint was HIV-1 RNA level decrease. Results Between April 2017 and August 2018, 101 patients were included from 31 hospitals. Most patients were men (93%), the median age was 36\hspace0.25emyears and 17% were Fiebig stage ≤q3. The median (IQR) plasma HIV-1 RNA and DNA levels were, respectively, 5.8 (5.0\textendash 6.6) and 3.87 (3.52\textendash 4.15)\hspace0.25emlog10 copies/million PBMCs. The median (IQR) decreases in HIV-1 DNA levels at W48 were -1.48 (-1.74 to -1.06) and -1.39 (-1.55 to -0.98)\hspace0.25emlog10 copies/million PBMCs in the dolutegravir and darunavir/cobicistat groups, respectively (P\mkern1mu=\mkern1mu0.52). Plasma HIV-1 RNA levels were <50\hspace0.25emcopies/mL in 24% versus 0% of patients in the dolutegravir and darunavir/cobicistat groups at W4, 55% versus 2% at W8, 67% versus 17% at W12, and 94% versus 90% at W48, respectively. Conclusions Dolutegravir-based and darunavir-based regimens initiated during PHI strongly and similarly decreased the blood reservoir size. Considering the rapid viral suppression during a period of high HIV-1 transmission risk, dolutegravir-based regimens are a major first-line option.