Cutaneous leishmaniasis (CL) is endemic in Campeche state, Mexico. Host and parasite factors are involved in the establishment and development of CL. Host factors include immune response and genetic background. NRAMP1 (Natural Resistance Associated Macrophage Protein 1) is important in innate immunity. Polymorphisms in NRAMP1 have been associated with susceptibility or resistance to infectious and autoimmune diseases. To study the association of NRAMP1 mutations with CL in patients from Calakmul, Campeche, samples from 115 CL patients and 69 samples of healthy people from the same area were evaluated. Five regions in NRAMP1 were amplified and digested, looking for mutations in the promoter region (-524G/C), exon 3 (274C/T), exon 8 (823 C7T), and exon 15 (G/A) and deletion of 4 bp in the 3'UTR region. We found a statistical association between polymorphisms in 3'UTR region and exon 8 and CL [χ2 = 13.26; p < 0.05; OR = 17.00; IC of 95% (2.24-128.99)]. Some patients who needed more than 40 doses of Glucantime® to heal injuries presented mutations in exons 3, 8, and 15. Multiple or ear lesions were not associated with NRAMP1 polymorphism.