This report describes a rare combined infection of Cryptococcus neoformans and Mycobacterium tuberculosis that manifested as a solitary pulmonary nodule in a nonimmunocompromised patient. Transthoracic needle aspiration biopsy was initially nondiagnostic, and histopathologic and culture confirmation of the diagnosis was eventually attained after wedge resection of the nodule. An extensive review of the English literature failed to reveal any reported cases of such a combined infection with a similar clinical presentation. The variable morphologic features of C. neoformans in tissue sections and the protean histologic features of pulmonary cryptococcosis can lead to diagnostic difficulties, as illustrated by this case.