The epidemiology of West Nile virus (WNV) in Israel is different from other neighbouring countries in the Middle East where disease burden has been minimal. We analysed a cohort of Ashkenazi Jewish patients with symptomatic WNV infection (n = 39), and WNV-negative controls (n = 61), for nine genetic variants that has been suggested to be associated with susceptibility to WNV. Two single nucleotide polymorphisms were significantly more frequent in WNV-infected than non-infected individuals, rs7280422 (MX1) [odds ratio (OR) 4·05, 95% confidence interval (CI) 2·04-8·03, P < 0·001] and rs3213545 (OASL) (OR 1·85, 95% CI 1·03-3·3, P = 0·03). Genetic polymorphism may play a significant role in susceptibility to WNV infection in Ashkenazi Jews.