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Behavioral factors increase the risk of contracting HIV. A comprehensive prevention services (CPS) intervention includes risk assessment and referral for those with confirmed risk. This project sought to assess the feasibility of an emergency department (ED)-based CPS program. A prospective cross-sectional assessment was conducted from October, 2021 through May, 2023, at a single ED in Birmingham, Alabama. Either of two screening methods were subjected to HIV negative adults: 1) manual chief complaint review or 2) objective electronic medical record (EMR) query. Manual and EMR screening methods considered sexually transmitted infections (STIs) or a positive urine drug test (to observe for commonly injectable drugs) within 12 months of current ED visit. Identified patients were approached in the ED (manual review) or via phone (EMR alert). Persons confirmed at risk for HIV following engagement questionnaire completion were made aware of their risk and offered referral to local CPS clinics. Primary outcome was CPS linkage. Descriptive analysis was performed. Of 184 patients approached, 147 agreed to engagement (79.9%), 117 in-person and 30 via phone; 125 (85.1%) were confirmed at risk for HIV; majority were white (66.4%), male (63.2%), between the ages of 30 and 49 (64.8%), uninsured (78.4%), and without a primary care provider (93.6%). Sexual behavior was identified as a recent (within six months) risk factor in 97 (77.6%) patients. Injection drug use was identified as a recent (within six months) risk factor in 71 (56.8%) patients. Fifty-four (43.2%) expressed interest in obtaining CPS follow-up. To-date, ten patients (18.5%) have connected with a CPS counsellor via phone and five (9.3%) have had a subsequent follow-up appointment to discuss CPS with a medical provider. Thirty at-risk patients (24.0%) received ED-initiated buprenorphine/naloxone. Targeted screening tools can aid in the identification of persons at risk for HIV in the ED; further, subsequent engagement and CPS implementation amongst this cohort is feasible. CPS clinic linkage may be challenging however, a CPS definition inclusive of ED-initiated medication for opioid use disorder, may offer opportunity for increased uptake., Competing Interests: The commercial funder does not alter our adherence to all PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Osman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)