BACKGROUND: Cerebral malaria (CM) is a serious complication of Plasmodium falciparum malaria that causes coma and frequently death in patients. In malaria-endemic settings, a large percentage of the population presents with incidental P. falciparum malaria parasitemia. In the absence of specific biomarkers for CM, when these individuals suffer from bacterial or viral infections causing coma, they are frequently misdiagnosed with CM. METHODS: We have tested the specificity for CM of two candidate biomarkers for severe malaria, Angiopoietin-like 4 and Inhibin-βE, which are secreted by endothelial cells in response to P. falciparum infected erythrocytes. The levels of these biomarkers were determined retrospectively in the plasma of a cohort of 379 Kenyan children including cases of severe malaria caused by CM, respiratory distress or severe anemia, as well as cases of non-traumatic coma of unknown cause. RESULTS: Angiopoietin-like 4 and Inhibin-βE showed high specificity for severe malaria, including CM (AUC 0.82), respiratory distress (AUC 0.86) and severe anemia (AUC 0.85), when compared to acute non-traumatic coma of non-malarial etiology. Specificity was further increased when the biomarkers were used in combination with platelet levels (AUC 0.96). Angiopoietin-like 4 and Inhibin-βE are also predictors of death by CM (AUC 0.85). CONCLUSIONS: Angiopoietin-like 4 and Inhibin-βE could be developed as a diagnostic tool for the differentiation of comatose patients with CM from other causes of coma.