A 58-year-old, alcoholic, diabetic man presented with multiple, ulcerated skin lesions and polymicrobial septicemia. Sporothrix schenckii was recovered from blood cultures and was resistant to amphotericin B by in vitro testing. Amphotericin B therapy failed, but the patient responded dramatically to itraconazole therapy, only to relapse 3 months after therapy was stopped. Reinstitution of itraconazole therapy has produced another dramatic response. This report is noteworthy for three reasons. First, to our knowledge, it represents only the second reported instance of fungemia with S schenckii that responded to medical therapy. Second, it illustrates that in vitro antifungal susceptibility tests may predict clinical infection response to drug therapy. Third, it suggests that itraconazole has significant promise in treating systemic sporotrichosis.