There are three potential pathogenetic routes to WHO-defined cerebral malaria (CM). The first, shown in red, is the classical pathway: a malaria infection evolves into retinopathy-positive (Ret+) CM. The second and third possibilities produce retinopathy-negative (Ret-) CM. In (a) the coma is entirely the result of another etiology and the malaria parasitemia is incidental. In (b), the coma is a product of the interaction between the malaria parasitemia and an additional cause (or causes) of coma. Sickle cell trait is underrepresented in patients with Ret+ and Ret- cerebral malaria (CM) because of the bottleneck at the transition between 'malaria infection' (asymptomatic malaria) and 'malaria disease' (uncomplicated malaria). Blood group O is underrepresented in patients with Ret+ CM, but not in those with Ret- CM. Taken together, the results for sickle cell trait and blood group O suggest that some Ret- CM cases occur through pathway (b) (because sickle cell trait is underrepresented in Ret- CM) and that malaria parasites contribute to the pathogenesis of these cases, and that sickle cell trait reduces the pathogenetic potential of malaria infection for Ret- CM but do not provide evidence that blood group O reduces the pathogenetic potential of malaria infection for Ret- CM.