A previously healthy Caucasian male developed hydropneumothorax and a pleural peel filled with pleomorphic, septate hyphae. The only organism grown from cultures of the lung and pleural fluid was Coccidioides immitis, confirmed by exoantigen testing. Spherule-endospore forms were produced, however, following injection of the arthroconidial tissue isolate into BALB/c mice. The patient had a positive immunodiffusion complement-fixation test and developed a positive coccidioidin skin test during therapy. He recovered following thoracotomy and wedge resection of the ruptured coccidioidal cavity, and therapy with amphotericin B followed by fluconazole. The sole presence of the mycelial form of the dimorphic fungus C. immitis in the pleural space may have been due to a low CO2 partial pressure at that site secondary to a bronchopleural fistula. The case shows a distinctive and uncommon presentation of coccidioidomycosis which demonstrates the specificity of both the immunodiffusion complement-fixation assay in diagnosing this disease and the exoantigen test in confirming culture results.