Semaglutide demonstrated significant anti-fibrotic effects in people with HIV, reducing liver fibrosis scores by 0.64 points in those with advanced disease (FIB-4 >2.67) after an average 218 days of treatment. Among 1,850 HIV patients across 10 clinical sites, the greatest improvements occurred in individuals with baseline moderate-to-advanced fibrosis, suggesting the drug's benefits extend beyond glycemic control to direct liver protection. This finding addresses a critical gap in HIV care, where metabolic dysfunction-associated liver disease has emerged as a leading cause of non-AIDS mortality. The HIV population faces unique challenges with liver fibrosis due to chronic inflammation, antiretroviral therapy effects, and higher rates of metabolic syndrome. While semaglutide's hepatoprotective mechanisms likely involve reduced hepatic steatosis and inflammation through GLP-1 receptor pathways, the observational design limits causal inference. The 80% prevalence of obesity and high rates of diabetes in this cohort reflect the metabolic burden facing aging HIV populations. These results suggest semaglutide could become a dual-purpose intervention, addressing both metabolic disease and liver fibrosis progression in HIV care, though randomized trials are needed to establish definitive efficacy.