Malaria has had a major effect on the human genome, many protective polymorphisms such as sickle cell trait having been selected to high frequencies in malaria endemicregions1,2. Recently, it was shown that the blood group variant Dantu provides 74%protection against all forms of severe malaria in homozygous individuals3-5. This is a similar degree of protection to sickle cell trait and considerably greater than the best malaria vaccine, but until now the protective mechanism has been unknown. Here, we demonstrate a significant impact of Dantu on Plasmodium falciparum-merozoite RBC invasion. Dantu was associated with extensive changes to the RBC surface protein repertoire, but unexpectedly, inhibition did not correlate with specific RBC-parasite receptor-ligand interactions. By following invasion using video microscopy, we found a strong link between RBC tension and merozoite invasion and identified a tension threshold above which invasion rarely occurred, even in non-Dantu RBCs. Dantu RBCs had higher average tension, meaning that a greater proportion resisted invasion. These findings provide both an explanation for the malaria-protective effect of Dantu, and fresh insights into why the efficiency of P. falciparum invasion might vary across the heterogenous populations of RBCs both within and between individuals.