The malaria hypothesis proposes that areas with high malaria transmission will have a high prevalence of malaria-protective haemoglobin variants [9]. However, epistatic interaction between genes has been described with malaria-protective genes, when the presence of one gene influences the phenotypic expression of another gene. Negative epistasis has been reported between sickle hemoglobin and α-thalassaemia, where their co-existence results in the loss of the malaria protection effect of either Hb variant [10]. In this study, we set out to explore the epistatic interaction between HbS and HbF on malaria in Tanzania, a country with a high prevalence of malaria and SCD.