Objective: Itraconazole is recommended as the first-line oral treatment for pulmonary histoplasmosis. There is a paucity of data describing hypersensitivity reactions to itraconazole and lack of clarity on triazole antifungal cross-reactivity. Case: Approximately 9 hours after an initial dose of itraconazole 200 mg for treatment of chronic cavitary pulmonary histoplasmosis, a 72-year immunocompetent patient developed anaphylactic symptoms that abated with intervention. To resume histoplasmosis treatment in the setting of limited treatment options following nephrotoxicity that occurred while receiving amphotericin B, a single posaconazole 100 mg tablet was given and well tolerated by the patient. Subsequently a treatment course of posaconazole 300 mg began with confirmation of therapeutic drug levels prior to hospital discharge. Imaging after 2 months of posaconazole showed improvement in cavitation size. Conclusion: Posaconazole was a safe and effective alternative to itraconazole for chronic cavitary pulmonary histoplasmosis in this case. Further evaluation of mechanisms and management of triazole hypersensitivity reactions are warranted.