Mycobacterium chelonae (formerly known as M. chelonae subspecies chelonae) is a rapidly growing mycobacterium that can cause disseminated infections, especially in immunocompromised hosts. The bacterium is typically resistant to antimicrobial agents; less than 20% of M. chelonae isolates are susceptible to trimethoprim-sulfamethoxazole, doxycycline, erythromycin, or ciprofloxacin. Findings in a recent study suggested that clarithromycin may be the drug of choice for the treatment of cutaneous (disseminated) disease due to M. chelonae. We describe a 60-year-old heart transplant patient with disseminated M. chelonae infection for whom monotherapy with clarithromycin failed because of the rapid development of resistance to the drug.