Non-cirrhotic portal hypertension (NCPH) has been recently reported as a liver disease in Human Immunodeficiency Virus (HIV)-infected patients under antiretroviral therapy (ART). Combination of non-exclusive mechanisms has been described: primary endothelial damage of terminal portal veins induced by HIV or immunologic disorders, mitochondrial toxicity by didanosine and prothrombotic state. It is characterized by heterogeneous liver histological findings, frequently identified as nodular regenerative hyperplasia and clinical manifestations of portal hypertension with well-preserved liver function. We describe herein two HIV-infected patients with clinical picture suggestive of NCPH. Besides the case reports, we briefly address questions to apply to patient care in clinical practice.