BACKGROUND: Hospitalizations for severe infections associated with substance use disorder (SUD) are increasing. People with SUD often remain hospitalized for many weeks instead of completing intravenous antibiotics at home; often, they are denied skilled nursing facility admission. Residential SUD treatment facilities are not equipped to administer intravenous antibiotics. We developed a medically enhanced residential treatment (MERT) model integrating residential SUD treatment and long-term IV antibiotics as part of a broader hospital-based addiction medicine service. MERT had low recruitment and retention, and ended after six months. The goal of this study was to describe the feasibility and acceptability of MERT, to understand implementation factors, and explore lessons learned. METHODS: We conducted a mixed-methods evaluation. We included all potentially eligible MERT patients, defined by those needing ≥2 weeks of intravenous antibiotics discharged from February 1 to August 1, 2016. We used chart review to identify diagnoses, antibiotic treatment location, and number of recommended and actual IV antibiotic-days completed. We audio-recorded and transcribed key informant interviews with patients and staff. We conducted an ethnographic analysis of interview transcripts and implementation field notes. RESULTS: Of the 45 patients needing long-term intravenous antibiotics, 18 were ineligible and 20 declined MERT. 7 enrolled in MERT and three completed their recommended intravenous antibiotic course. MERT recruitment barriers included patient ambivalence towards residential treatment, wanting to prioritize physical health needs, and fears of untreated pain in residential. MERT retention barriers included high demands of residential treatment, restrictive practices due to PICC lines, and perceptions by staff and other residents that MERT patients “stood out” as “different.” Despite the challenges, key informants felt MERT was a positive construct. CONCLUSIONS: Though MERT had many possible advantages; it proved more challenging to implement than anticipated. Our lessons may be applicable to future models integrating post-hospital intravenous antibiotics and SUD care.