Erythema Nodosum Leprosum (ENL) is an acute and systemic inflammatory reaction of leprosy characterized by painful nodules and involvement of various organs. Thalidomide is an immunomodulatory and anti-inflammatory drug currently used to treat conditions such as ENL and multiple myeloma (MM). Cereblon protein was described as the primary target of thalidomide teratogenicity. Moreover, it was postulated that CRBN is necessary for the efficacy of thalidomide and its analogs in the treatment of MM. In this study, we evaluate the influence of CRBN genetic variants on the dose of thalidomide used in the treatment of ENL and on the manifestation of adverse effects during treatment for ENL. Polymorphisms rs1620675, rs1672770 and rs4183 located in regions flanking the part of the gene encoding the portion of the protein that binds to thalidomide were evaluated. An association with adverse ocular and gastrointestinal effects was observed. These results show that CRBN polymorphisms could alter the expression or activity of the protein and influence the development of adverse effects in response to thalidomide in ENL.