WHAT IS KNOWN AND OBJECTIVE?: Antiretroviral (ARV) resistance may result during periods of consistently poor adherence. We report the successful use of a novel once-daily (QD) ARV regimen in a patient with multidrug-resistant (MDR) HIV. CASE SUMMARY: Once-daily darunavir 1200 mg/ritonavir 100 mg, dolutegravir and emtricitabine/tenofovir alafenamide was initiated with directly observed therapy. With the assistance of therapeutic drug monitoring, dolutegravir dosing was increased to 150 mg daily. The patient maintained virologic suppression for 18 months. WHAT IS NEW AND CONCLUSIONS?: In this case, QD darunavir/ritonavir achieved similar trough concentrations to twice daily dosing with dolutegravir dose titration necessitated and resulted in HIV virologic control.