Histoplasmosis is an endemic fungal infection caused by the dimorphic fungus, Histoplasma capsulatum, which is treated with intravenous amphotericin B and oral itraconazole as first-line and second-line therapy. We report a case of a man in his early 70s treated with methotrexate and infliximab for rheumatoid arthritis who developed disseminated histoplasmosis. The patient was unable to absorb itraconazole due to intractable diarrhoea and developed a severe, anaphylactoid reaction or an immune reconstitution inflammatory syndrome when treated with liposomal amphotericin B. He was subsequently treated with isavuconazole and steroids and made a full recovery.A literature review revealed other cases of histoplasmosis which were treated with isavuconazole including both primary pulmonary and disseminated presentations. Cases of blastomycosis which were treated with isavuconazole are also reviewed including those with severe immunocompromised statuses including solid-organ transplant and tumour necrosis factor-alpha antagonist recipients. Our report describes the potential role of isavuconazole in cases of histoplasmosis where first-line and second-line therapies have failed or are contraindicated (excluding meningitis).