Nocardia species is a well-known pathogen in immunocompromised hosts, including renal transplant recipients. Primary pulmonary infection can disseminate to other organs and recommended first-line therapy is high-dose trimethoprim/sulfamethoxazole (TMP/SMX). We report two cases of primary pulmonary Nocardia sp. in immunosuppressed patients who were treated with minocycline, a second-line drug. During treatment with minocycline, both patients developed central nervous system (CNS) lesions of Nocardia sp. and were then treated with TMP/SMX with resolution of disease. The literature on Nocardia and treatment with minocycline is reviewed. Treatment of pulmonary Nocardia sp. with 200 mg minocycline daily is not adequate to prevent disseminated CNS disease.