The replication of the association study between NOD2 rs8057341 in different populations from Brazil (Rondonópolis, Bauru, and Rio de Janeiro) was observed in all case–control samples, with the AA genotype conferring resistance to leprosy (P = 1.39 × 10−6; OR = 0.49; IC = 0.36–0.65), but the same results were not observed in the family-based study. This evidence concerns the gene NOD2 and leprosy.