Leishmaniasis, a disease caused by protozoan spp., exhibits a broad range of clinical manifestations. Host resistance or susceptibility to infections is often influenced by the genetic make-up associated with natural immunity. Caspase-1, a key component of the NLRP3 inflammasome, is critical for processing pro-IL-1β into its active form, IL-1β, while CARD8 functions as an NLRP3 inflammasome inhibitor. We conducted a case-control study comparing -cutaneous leishmaniasis (-CL) patients with healthy individuals (HCs) by analyzing the genetic variants rs530537A>G, rs531542C>T, rs531604A>T and rs560880G>T. Additionally, a combined analysis of rs2043211A>T with rs530537 was performed. The genotype distribution for the four variants showed no significant differences between -CL patients and HCs. However, the haplotype analysis of the four variants identified the GTTT haplotype as associated with a 19% decreased likelihood of -CL development, suggesting a protective effect against disease progression. The combined analysis of with variants indicated that individuals homozygous for both variants (GG/TT) exhibited a 38% reduced risk of developing -CL (OR = 0.62 [95%CI:0.46-0.83]) in comparison to individuals with other genotype combinations. No correlation was found between the CASP1 variant genotypes and plasma IL-1β levels. may act as a genetic modifier in -CL.