BACKGROUND: The vitamin D pathway contributes to the microbicidal activity of macrophages against infection. In addition to induction of this pathway, interferon-gamma (IFNγ), interleukin (IL)-15, and IL32γ are part of a network of pro-inflammatory cytokines. The aim of this study was to evaluate single-nucleotide polymorphisms (SNPs) in the components of the vitamin D pathway and associated cytokine genes that could be related to resistance or susceptibility to American tegumentary leishmaniasis (ATL). METHODS: The expressions of , , , , , and other pro-inflammatory cytokines , , and genes were evaluated using real-time polymerase chain reaction (qPCR) in lesions of patients with localized cutaneous leishmaniasis (LCL) or mucosal leishmaniasis (ML). SNP genotypes/alleles (in , , , and ) were evaluated by TaqMan PCR assays using DNA from the blood of patients and healthy individuals. Serum vitamin D levels were determined by chemiluminescence. RESULTS: Vitamin D pathway-associated genes were expressed in cutaneous as well as mucosal lesions. , , and were more highly expressed in ML than in LCL. In contrast, mRNAs were mainly correlated in LCL, and in ML makes strong connections with all cytokines. The SNP rs1555001 was less frequent in patients with ML. In addition, some SNPs appear to influence the and ( rs10519613 and rs3775597) and ( rs7975232) expressions in LCL and the expression in ML ( rs3775597). Gene expression was also correlated with clinical parameters, such as number of lesions ( mRNA) and treatment failure ( mRNA). In addition, one SNP was associated with treatment failure in ML ( rs7975232). CONCLUSIONS: Our findings suggested that some SNPs in the vitamin D pathway-associated genes can be related to resistance and therapeutic outcomes of ATL. They are promising candidates that need to be further evaluated to understand their biological effects in the control or immunopathogenesis of ATL.