Severe hepatotoxicity is a rare but potentially life-threatening side effect of antiretroviral therapy. In this case report we describe an HIV-positive patient who was admitted to our clinic with evidence of severe acute pancreatitis 18 months after the introduction of antiretroviral treatment, which included stavudine and didanosine. Shortly afterwards, she developed lactate acidosis and acute hepatic failure associated with renal failure. Renal support (hemofiltration) was required for three days. The patient subsequently developed grade III encephalopathy, as well as a large pleural effusion and ascites. Although the reported outcome of patients with liver failure due to antiretroviral treatment is poor, with a high mortality rate, our patient fully recovered after intensive supportive care and cessation of the antiretroviral agents. Liver biopsy revealed microvesicular steatosis and giant mitochondria, which are the typical hallmarks of mitochondrial damage, the presumed mechanism of antiretroviral drug toxicity. More than three years later the patient has an excellent clinical status with a stable HIV infection and no need for antiretroviral treatment. This case report indicates the need for increased awareness of the potential hepatotoxicity of an antiretroviral therapy, as severe side effects may occur more frequently with increasing use of such treatment.