Intravenous amphotericin B remains the most effective drug for eradicating Prototheca infections. It should be used as a first-line agent in cases of disseminated disease and in patients with severe underlying illness or with immunosuppression or immunocompromise. Azole antifungals and surgery should be reserved for patients with more localized disease. Itraconazole appears to be the most effective agent of this drug class, and it should be administered at 200 mg/day for 2 months. Surgical excision should be considered as a first-line therapy in patients who present with olecranon bursal infections.