In leprosy, type 1 reaction (T1R) and type 2 reaction (T2R) are major causes of nerve injury and permanent disabilities. A previous study on plasma levels of 27 cytokines in patients with T1R or T2R and controls with nonreactional leprosy identified the gene for interleukin 6 (IL-6) as a candidate for genetic analysis. Two nested case-control studies were built from a cohort of 409 patients with leprosy from central Brazil, monitored for T1R and T2R. There was evidence for association between T2R and IL-6 tag single-nucleotide polymorphisms rs2069832 (P = .002), rs2069840 (P = .03), and rs2069845 (P = .04), with information on the entire IL-6 locus, as well as functional IL-6 variant rs1800795 (P = .005). Moreover, IL-6 plasma levels in patients with T2R correlated with IL-6 genotypes (P = .04). No association was found between IL-6 variants and T1R. Identifying genetic predictive factors for leprosy reactions may have a major impact on preventive strategies.