Hepatitis E virus (HEV) infection is responsible for major endemic outbreaks in developing countries. Human immunodeficiency virus (HIV) and HEV are widespread in the Central African Republic. We report the first documented case of an HEV infection in a 36-month-old child already suffering from HIV and severe acute malnutrition (SAM). The HIV patient was hospitalized for SAM with persistent diarrhea and prolonged fever. The presence of IgG anti-HEV antibodies was noted. Sequencing of the amplified HEV RNA revealed the presence of genotype 3c. The alanine aminotransferase level was slightly above average. The patient died despite being treated by antiretroviral therapy accompanied by probabilistic antibiotic therapy and nutritional rehabilitation. HEV/HIV co-infection in a malnourished patient can accelerate a fatal outcome. In the presence of biological abnormalities in a severe acutely malnourished HIV-infected patient, HEV RNA detection should be added to the standard medical assessment in sub-Saharan African countries.