Background: Homelessness is an important social determinant of health (SDOH), impacting health outcomes for many medical conditions. Although homelessness is common among people with opioid use disorder (OUD), few studies systematically evaluate homelessness and other SDOH among people enrolled in standard of care treatment for OUD, medication for opioid use disorder (MOUD), or examine whether homelessness affects treatment engagement. Methods: Using data from the 2016 to 2018 U.S. Treatment Episode Dataset Discharges (TEDS-D), patient demographic, social, and clinical characteristics were compared between episodes of outpatient MOUD where homelessness was reported at treatment enrollment versus independent housing using pairwise tests adjusted for multiple testing. A logistic regression model examined the relationship between homelessness and treatment length and treatment completion while accounting for covariates. Results: There were 188 238 eligible treatment episodes. Homelessness was reported in 17 158 episodes (8.7%). In pairwise analysis, episodes involving homelessness were significantly different from those involving independent living on most demographic, social, and clinical characteristics, with significantly greater social vulnerability in most SDOH variables ( P’s < .05). Homelessness was significantly and negatively associated with treatment completion (coefficient = −0.0853, P < 0.001, 95% CI = [−0.114, −0.056], OR = 0.918) and remaining in treatment for greater than 180 days (coefficient = −0.3435, P < 0.001, 95% CI = [−0.371, −0.316], OR = 0.709) after accounting for covariates. Conclusions: Patients reporting homelessness at treatment entry in outpatient MOUD in the U.S. represent a clinically distinct and socially vulnerable population from those not reporting homelessness. Homelessness independently predicts poorer engagement in MOUD confirming that homelessness may be an independent predictor for MOUD treatment discontinuation nationally.