Abstract Concomitant administration of azole antifungal agents and rifamycins is contraindicated because an interaction between these drugs results in subtherapeutic azole concentrations. We describe a 30-year-old woman with severe pulmonary disease associated with Mycobacterium xenopi and Aspergillus fumigatus, necessitating simultaneous antimycobacterial and antifungal therapy. She was treated with rifabutin-the rifamycin with the least cytochrome P450 (CYP) enzyme induction-and therapeutic drug monitoring was performed so that target serum concentrations of all antimicrobial agents could be achieved. As a result of this monitoring, the frequency of voriconazole 300 mg needed to be increased from twice/day to 3 times/day. The patient's clinical outcome improved dramatically. She was discharged from the hospital and continued treatment for her mycobacterial infection while remaining free of the Aspergillus infection. We believe that careful drug selection combined with therapeutic monitoring of antimicrobial drug serum concentrations is a practical model that clinicians can use to manage coexisting mycobacterial and fungal infections.