Byline: Constantina Politis, Myrsini Parara, Jenny Kremastinou, Eleni Hasapopoulou, Aliki Iniotaki, Alexandra Siorenta, Clive Richardson, Anna Papa, Lilian Kavallierou, Marina Asariotou, Olga Katsarou, Athina Mougiou, Lukas Dadiotis, Zafeiria Alexandropoulou, Angelica Megalou, Evangelia Magoula, Margarita Papadopoulou, Danai Pervanidou, Agoritsa Baka, Christos Hadjichristodoulou BACKGROUND West Nile virus (WNV) infection, commonly asymptomatic, may cause mild West Nile fever (WNF) or potentially fatal neuroinvasive disease (WNND). An outbreak of 262 cases of the new Lineage 2 strain in Greece in 2010 continued with high mortality (17%) in WNND. The objective was to investigate ABO, D, and Lewis blood groups, as well as HLA Class I and Class II alleles, in relation to WNV Lineage 2 disease morbidity. STUDY DESIGN AND METHODS A cohort of 132 Greek WNV cases in 2010 to 2013 (65% male; mean age 64 years; 41% WNF, 59% WNND) was compared to 51,339 healthy WNV-negative blood donors and 246 healthy subjects. RESULTS Blood group A was more common in WNV cases (51%) than blood donors (39%) and group O less common (32% vs. 42%). D negativity within group A was higher in WNV than in blood donors (18% vs. 10%, p=0.044). The frequency of secretors (Lewis(a-b+)) was 60% in WNV and 68% in donors (p=0.16). HLA alleles C*08, DRB1*O4:O5, and DQB1*O2 occurred significantly less frequently in WNV than controls (p CONCLUSION This first study of symptomatic WNV Lineage 2 suggests A/D negativity as a new risk factor associated with WNV infection and level of morbidity. Further studies are required of the possibility that HLA C*08, DRB1*O4:O5, and DQB1*O2 are protective alleles and DRB1*10:O1 a "susceptible" allele to WNV infection and the role of secretor status in relation to WNV infection. Article Note: *Data are reported as number (%).