Single-nucleotide polymorphisms within the genes coding for tumor necrosis factor (TNF)-alpha and interleukin (IL)-10 have been associated with several infectious diseases. To determine whether such polymorphisms are associated with leprosy, genotyping was performed at the -308 and -238 positions of the promoter of the TNF-alpha gene in 210 and 191 patients with multibacillary (MB) leprosy, respectively; 90 and 79 patients with paucibacillary (PB) leprosy; and 92 control subjects. For the -592 and -819 positions within the promoter of the IL-10 gene, 143 patients with MB leprosy, 79 patients with PB leprosy, and 62 control subjects were included in the analysis. TNF2 allele frequency was significantly higher among control subjects than among all patients with leprosy or in the MB group (P<.05 and P<.01). For the IL-10 gene, the frequency of the homozygous -819TT genotype was significantly higher among patients than among control subjects. These data indicate that a relationship exists between TNF-alpha and IL-10 promoter polymorphisms and the development of PB leprosy.