We report a case of severe lactic acidosis in an human immunodeficiency virus (HIV)-infected patient treated with combination regimen of stavudine, didanosine and nevirapine. Antiretroviral nucleoside analogs are inhibitors of mitochondrial DNA polymerase gamma, resulting in the dysfunction of the mitochondrial respiratory chain. Despite symptomatic treatments and intravenous L-carnitine supplementation, lactic acidosis persisted, leading to multiorgan failure. The patient died 7 days after admission to the intensive care unit. Retrospective analysis of published cases showed neither specific nor predictive signs of outcome that is usually fatal, with no effective therapy to date. We therefore recommend determining blood lactate in patients with onset of unexplained general fatigue or digestive signs and to stop all antiretroviral treatments in the case of lactate increase.