In this case-control study, we enrolled 4,555 individuals and investigated whether PKLR single nucleotide polymorphisms (SNPs) putatively selected for malaria resistance are associated with susceptibility to leprosy across Brazil (Manaus–North; Salvador–Northeast; Rondonópolis–Midwest and Rio de Janeiro–Southeast) and with tuberculosis in Mozambique. The gene discussed is PKLR; the disease is malaria.