Buruli ulcer is a chronic and infectious skin disease, caused by Mycobacterium ulcerans. It leads to large skin ulceration and sometimes bone infection which is responsible for deformities. Here, we report a case of multifocal form of Buruli ulcer associated with secondary infection in a 46-year-old human immunodeficiency virus (HIV) positive woman. The antimycobacterial drugs combined to surgery allowed curing this multifocal case and rose up two relevant issues: the susceptibility of immune reconstitution inflammatory syndrome (IRIS) occurrence and Mycobacterium dissemination. The deep immune depression, the underline biological, and clinical disorders of the patient might contribute to IRIS occurrence and Buruli ulcer dissemination. Future investigations have to be conducted on the mechanism of IRIS on set and on Mycobacterium ulcerans dissemination after ARV drugs initiation and the patient related underline clinical or biological disorders.