A skin biopsy sample was obtained from a relapsed lepromatous leprosy patient from the central area of Mexico. Genes associated with resistance to anti-leprosy drugs were analyzed by DNA sequence assay. A single nucleotide substitution was found at codon 53 (ACC-->GCC) in the folP gene, which is known to confer dapsone resistance. No mutations in the rpoB and gyrA, which indicate resistance to rifampicin and fluoroquinoles, were detected. This is the first reported case of dapsone resistant leprosy in Mexico in which the cause of the resistance is shown at genomic level. Evaluation of drug resistance by identifying known mutations in these genes by PCR is simple and reliable. Testing for resistance to anti-leprosy drugs should be performed in relapses or intractable cases for a better outcome.