Abstract. At the end of World War I, British medical officers noted that soldiers infected with malaria were more likely to die during the 1918 influenza pandemic than those without malaria. This synergistic mortality appeared to be specific to Plasmodium falciparum and has not been generally noted since 1920. A possible explanation is that a malariainduced procoagulant state enhanced the activation of influenza virus to increase inflammation and subsequent severe clinical outcomes. Falciparum proteins bind and likely inhibit antithrombin 3 and other factors. Pathogens interact in ways that may inform pathophysiology studies of remote epidemics.The co-existence of a malarial infection seemed to render the patient extremely susceptible to this post-influenzal pneumonia and to lower his chance of recovery from it almost to vanishing point. (W Angus, Palestine 1919) 1 The influenza pandemic of 1918 killed more people than died during World War I.2 Although influenza pandemics have reappeared intermittently, the extreme mortality of influenza in 1918-1920 has never been well explained, especially its unique concentration in young adults from 20 to 40 years of age.3 During World War I, British Army soldiers were severely affected by malaria in Palestine (modern Israel/Jordan/Syria), Macedonia (modern Greece), and Mesopotamia (modern Iraq). When the influenza pandemic arrived at the end of the war, severe clinical outcomes were observed nearly everywhere, but some of the highest mortality rates were in soldiers simultaneously infected with falciparum malaria. Although limited by the laboratory resources available in that era, keen clinical observers detected synergistic mortality between falciparum malaria and pandemic influenza in all the three countries and confirmed their findings with postmortem studies. [4][5][6] That the two pathogens might increase mortality when they simultaneously infected the same person was not surprising, but the independently reported mortality of dually infected soldiers was so great as to raise questions regarding the pathophysiology especially because this effect has not been observed since 1920. Insight may be obtained by constructing plausible scenarios based on modern understanding of infection and inflammation specifically Plasmodium falciparum's effect on the coagulation cascade. An interaction between parasite and viral proteins is hypothesized to be a likely explanation of synergistic mortality during the influenza pandemic of 1918.The increased mortality of combined influenza and malaria infections was spontaneously noted by the medical officers in 1918 despite the very different military and public health situations in Palestine, Macedonia, and Mesopotamia. [4][5][6] Postmortem studies in Palestine by Fairley showed 59% of 80 malaria deaths complicated by influenza, in Egypt MansonBahr observed 48% of 67 malaria deaths complicated by influenza and in Macedonia out of 100 deaths due to influenza, 83% also had malaria infection. [4][5][6] The massive number of casualties occurri...