A lower limb ulcer is a disabling disease with significant functional impact and difficulties to manage. Ulcers, due to infectious agents, an inflammatory etiology, or microvascular occlusion are particularly challenging in terms of diagnosis and treatment. The management of such ulcers requires proper clinical examination as well as oriented biological and histological assessments. Herein, we report the case of a 39-year-old female from Ivory Coast with an extensive bilateral lower limb ulcer evoking a Buruli’s ulcer. Investigations, however, revealed a severe case of pyoderma gangrenosum in an HIV-positive patient. Our case report demonstrates the difficulties in the diagnosis of leg ulcers, especially in immunosuppressed patients. Confusing pyoderma gangrenosum with a Buruli’s ulcer may lead to extensive surgery or the use of long-term steroids with multiple iatrogenic complications, hence the importance of a skin biopsy and biological assessments in establishing a correct diagnosis.