Populations exposed to Plasmodium falciparum infection develop genetic mechanisms of protection against severe malarial disease. Despite decades of genetic epidemiological research, the HbAS sickle polymorphism, ABO blood group and other haemoglobinopathies remain the few major determinants in severe malaria to be replicated across different African populations and study designs. Set within a case-control study in a region of high transmission in Tanzania (n=983), we investigated the role of 40 new loci identified in recent genome-wide studies. In 32 loci passing quality-control procedures, we found polymorphisms in USP38, FREM3, SDC1, DDC, and LOC727982 genes as being putatively associated with differential susceptibility to severe malaria. Traditional candidates explained 7.4% of variation in severe malaria risk (HbAS polymorphism 6.3%, alpha-thalassaemia 0.3%, ABO group 0.3%, and glucose-6-phosphate-dehydrogenase deficiency 0.5%) and the new polymorphisms, a further 4.3%. The regions encompassing the loci identified are promising targets for the design of future treatment and control interventions.