Background & Aim: Liver disease, which is predominantly caused by Hepatitis C virus (HCV) infection, represents the second major cause of death in HIV-positive patients. Thus, there is a need to understand the determinants of liver disease progression in HIV/HCV coinfected patients. Previous studies demonstrated that immune status as well as endocrine, metabolic and genetic factors all contribute to liver disease in HIV patients. However, data for HIV/HCV coinfection is limited and none of the previous studies considered all of these factors. Thus, we aimed to investigate the independent roles of serum 25(OH)D levels, insulin resistance (IR), immune status, IL28B, and PNPLA3 on liver fibrosis progression in HIV/HCV coinfection. In addition, we assessed their impact on portal pressure, which drives the development of complications.Patients & methods: 86 patients were included in this study. Determinants of portal pressure were analyzed in a subgroup of 71 patients with available data on hepatic venous pressure gradient (HVPG). Liver fibrosis progression rates were calculated assuming a linear course model: METAVIR F units divided by the number of years since infection. Those with a FPR > median FPR were assigned to the highFPR group.Results: The median FPR was 0.167 units/year. The prevalence of prior alcohol abuse, low CD4+ T-cell nadir and 25(OH) vitamin D deficiency was greater in the highFPR group, while insulin resistance and IL28B genotype distribution were comparable. The only four patients with the unfavorable PNPLA3 G/G genotype were observed in the highFPR group, but due to the small sample size PNPLA3 was excluded from further analysis. In multivariate analysis only 25(OH) vitamin D deficiency and low CD4+ T-cell nadir were independently associated with fibrosis progression. Portal pressure correlated with alcohol abuse, HCV genotype 3, CD4+ T-cell nadir and 25(OH) D levels.Conclusion: Two potentially modifiable factors, 25(OH) vitamin D deficiency and a low CD4+ T-cell nadir independently modulate fibrosis progression and determine portal pressure in HIV/HCV coinfection.