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Introduction People living with HIV (PLWH) in vulnerable and marginalized conditions face substantial barriers to HIV care, resulting in reduced ART adherence, loss to follow-up, and higher risks of virological failure and mortality.Methods This retrospective study evaluates a residential care and/or home-based assistance model for highly vulnerable PLWH, led by Caritas Roma. The intervention includes multidimensional needs assessment, ART adherence monitoring, clinical follow-up, support to specialist visits, and health education. Clinical, behavioral, and social data were analyzed to assess effects on retention in care, ART adherence, and immuno-virological outcomes over 2015-2025.Results The study included 106 PWLH ( table 1), mostly male (60.4%) and Italian (77.4%). Most were unemployed (66.7%), and only 57.8% had stable housing. Alcohol use was reported by 37.9%, smoking by 85.7%, substance use history (PWID) by 54.6%, and psychiatric disorders by 69.4%, more frequently among patients in residential care. Compared with patients who received home-based assistance, those in residential care were younger, had longer HIV history, and were more often non-Italian, unemployed, and housing-unstable. They also reported higher lifetime exposure to violence and were less likely to have a caregiver (all p < 0.01).The main risk factor for HIV infection was PWID (53.7%) (table 2). Most patients were in CDC stage C3 (62.5%) with a CD4 nadir <200 cells/mm3 (80.2%). Factors associated with lack of adherence to ART in univariate analysis were younger age at diagnosis, being unemployed compared with being retired, housing instability, alcohol use, PWID, psychiatric disorders, and detectable viral load (>50 copies/mL) at entry into care.Comparing the immuno-virological profile at entry and at the most recent available tests, CD4 lymphocyte count significantly increased at the last examination (431 vs 530 cells/mm3, p < 0.001), while the proportion of patients with CD4 count <200 cells/mm3 (29.8% vs 7.6%) decreased. The percentage of patients with detectable viral load (>50 copies/mL) significantly decreased from 23.6% at entry to 5.4% at the last available tests.At the end of follow-up, 16 patients were discharged or no longer followed by the service due to lack of indication, 65 patients were still under care, 16 were transferred to other services, 6 had died, and 6 were lost to follow-up.Discussion This study provides concrete evidence of the effectiveness of an integrated residential intervention and home-based assistance in a complex population living with HIV. The findings may contribute to the development of sustainable, multidisciplinary, and person-centered strategies, particularly for the most vulnerable patients engaged in social inclusion programs, with potential benefits including improved public health outcomes, reduced inequalities, and optimized resource use.Abstract SC28 Table 1–2