OBJECTIVES: Patients with dengue exhibit a range of symptoms from an acute febrile illness (dengue fever, DF), to dengue hemorrhagic fever (DHF), and to the most severe outcome, dengue shock syndrome (DSS). This study was performed to determine the host genetic factors responsible for dengue severity. Two single nucleotide polymorphisms (SNPs) of the interferon lambda 1 (IFNL1) gene (rs30461 and rs7247086) were analyzed for their association with dengue severity in a Thai population. METHODS: This was a case-control association study involving 877 patients under the age of 15 years (DF, n = 386; DHF, n = 416; DSS, n = 75). Genotyping was performed by TaqMan real-time PCR assay. RESULTS: It was found that the rs7247086 variant of IFNL1 was associated with DHF, but not DSS. Genotypes CT and TT and the T allele were protective against DHF (p = 0.03, odds ratio 0.62 for CT, odds ratio 0.13 for TT; and p = 0.01, odds ratio 0.54 for the T allele). The other SNP tested was not associated with DHF or DSS. CONCLUSIONS: The rs7247086 variant of IFNL1 (the T allele) was found to be protective against DHF, suggesting that IFNL1 may play a role in the pathogenesis of DHF.