Introduction: Many infectious disease intervention programs, including leprosy, are cautious about the establishment of relapse and drug resistance. This case report reports on a male patient who has had two relapses and had undergone twice MB-MDT treatment as well.
 Case Report: A 31 year-old male, came with the main complaint of new hypopigmented patches appeared on the body since 4 months ago, which arose from his second MB-MDT treatment. He started his first MB-MDT treatment in 2019 and second MD-MDT in 2020. Slit skin smear yielded negative results and histopathological examination showed no signs of leprosy. Serological anti-PGL-1 antibody tests yielded very high IgM (3.163) and normal IgG (2) levels. PCR amplification examination showed positive, but DNA sequencing targeting rpoB, folP, and gyrA genes showed no mutations. He was diagnosed with persisters relapse in a borderline-lepromatous leprosy and was treated with rifampicin 600 mg/day for 2 weeks; combination of minocycline 100 mg/ day, clarithromycin 500 mg/ day, and clofazimine 50 mg/ day for 6 months; and methylprednisolone 32 mg/ day for the neuritis. No new lesions appeared during current treatment and he is also showing gradual improvement of foot drop in his left leg.
 Discussion: The fact of a very high IgM levels after 2 courses of MB-MDT indicated that there is still bacteria that continued to induce antibody formation, thus supporting the persisters bacilli hypothesis in this case. Positive results of PCR amplification conclude that there is still M. leprae bacilli in skin tissues, which may be hidden in deeper tissues. We have to make a more proactive approach considering this was his second times of relapse, and knowing the fact that MB-MDT was consumed religiously in the two previous treatment.
 Conclusion: In an arduous case like this, proactive step must be taken. Whenever possible, the use of whole genome sequencing is strongly advised.
 Keywords: leprosy, persisters bacilli, relapse, drug resistance