We examined the longitudinal association between alcohol use and liver fibrosis, measured by FIB-4 Score, among HIV-infected individuals by (1) antiretroviral therapy (ART) class, and (2) the presence of hepatitis C (HCV) co-infection. This was a prospective cohort study of 550 individuals in the Johns Hopkins HIV Clinical Cohort initiating ART between 2000 and 2012. The relationship between alcohol consumption (defined using NIAAA categories of non-, moderate, and hazardous drinkers) and liver fibrosis (FIB-4 score) by ART class was assessed using linear mixed effects models. Additionally, we examined whether the presence of HCV modified and whether viral load mediated the relationship between alcohol use and liver fibrosis. Overall, FIB-4 levels were 15.6% higher in hazardous drinkers compared to moderate drinkers (p = 0.025) after adjusting by age, sex, and race. Hazardous drinkers on PI-based regimens had FIB-4 scores 26.9% higher than moderate drinkers (p = 0.015). However, there was no difference in FIB-4 levels between hazardous drinkers on non-PI-based regimens compared to moderate drinkers (1.83% versus moderate drinkers, p = 0.848). There was no significant difference in FIB-4 between nondrinkers and moderate drinkers, irrespective of ART regimen. These associations were not modified by HCV status or mediated by viral load changes. Individuals with hazardous alcohol consumption and on PI-based regimens had significantly increased liver fibrosis, as measured by the FIB-4. These data suggest that providers should consider level of alcohol consumption when choosing an ART regimen to minimize detrimental effects on the liver.