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Episodes of human immunodeficiency virus low-level viremia (LLV) are common in the clinical setting, but its association with antiretroviral therapy (ART) regimen and adherence remains unclear. Antiretroviral therapy adherence was evaluated in participants of the Research on Access to Care in the Homeless cohort by unannounced pill counts. Factors associated with increased risk of LLV include treatment with a protease inhibitor (PI)-based regimen (ritonavir-boosted PI vs nonnucleoside reverse-transcriptase inhibitor: adjusted hazard ratio [HR], 3.1; P = .01) and lower ART adherence over the past 3 months (HR, 1.1 per 5% decreased adherence, adjusted; P = .050). Patients with LLV may benefit from ART adherence counseling and potentially regimen modification.