African histoplasmosis is a granulomatous mycosis caused by Histoplasma capsulatum var. duboisii. Treatment is usually extrapolated from guidelines for classical histoplasmosis, and includes 2-4 weeks of amphotericin B followed by a step-down maintenance therapy with itraconazole. Pediatric usage of posaconazole, an oral second-generation azole, remains off-label, but recent surveys show that it is safe and well tolerated in children. We report a case of disseminated African histoplasmosis in a 12-year-old boy from Guinea-Bissau. Therapy with amphotericin B and itraconazole led to a progressive clinical deterioration. A dramatic and lasting improvement was observed using posaconazole. He completed 12 months of therapy. No relapse was noted during or 3 months after treatment. We report that posaconazole may be a safe and efficacious drug in the salvage management of disseminated AH, either in patients with disease refractory to conventional anti-fungal therapy, or in patients whose serious adverse effects of first-line drugs preclude its use.