Jorge Lobo’s disease (JLD) is a chronic, granulomatous fungal infection caused by the traumatic implantation of the fungus Lacazia loboi in the cutaneous and subcutaneous tissues, with the presence of isolated nodular and coalescent keloidal lesions. Malignant degeneration is rare. This case report describes a 64-year-old male patient with JLD for 30-years who showed a change in the aspect of a lesion in the left lower limb. Histopathological examination confirmed the progression to well-differentiated squamous cell carcinoma (SSC). JLD is highly prevalent in tropical and subtropical regions, requiring monitoring concerning the transformation into SSC in long-term lesions.