Background: Antiretroviral directly observed therapy, in which nurses or other allied health professionals provide patients with daily medication, is an evidence-based solution for viral load suppression in people living with HIV who experience homelessness. Purpose: This quality improvement project aimed to assess the outcomes of antiretroviral directly observed therapy at one urban clinic caring for people living with human immunodeficiency virus who experience homelessness and substance use disorder. Methods: Data was collected from the electronic health record for the antiretroviral directly observed therapy patient cohort (n = 33); 10 of them were surveyed. Fisher exact tests determined nonrandom associations between viral suppression and all other categorical variables. Survey answers were mapped to the modified Andersen’s Behavioral Model domains and subcategories. Results: Seventy-three percent of program patients were virally suppressed after participating in the program; 42% were virally undetectable. The relationship between viral suppression and date of most recent primary care provider visit was significant (p = 0.01). Eighty percent of surveyed patient participants reported that they liked the program, and 70% said that taking ART makes them feel better. Eighty percent of patients described their health as “Fair” or “Poor” before initiating treatment with the program, while 90% of patients reported their own health as being “good”, “very good”, or “excellent” after participating. Conclusion: Results suggest that when nurse-led teams actively engage PLWH, viral suppression, and consequent undetectability, is more likely. Clear implications for practice include continuing nurse navigation to promote viral suppression.