A 66-year-old man with HIV and recurrent thromboembolism presented with new-onset ascites with an extensive diagnostic work-up that was unremarkable. He was diagnosed with non-cirrhotic portal hypertension after a liver biopsy revealed mild fibrosis and hepatic venography revealed an elevated hepatic venous pressure gradient. The etiology of portal hypertension was attributed to didanosine therapy, a rare but noted side effect.