Nocardia transvalensis, a rare Nocardia species, has previously been recognized as a cause of actinomycotic mycetoma. In a retrospective review of N. transvalensis isolates referred to the Centers for Disease Control (Atlanta) during the period January 1981 through January 1990, we identified 15 patient isolates. Four N. transvalensis isolates originated from one Australian reference laboratory; one patient's isolate that was identified by the Australian laboratory but that was not received at the Centers for Disease Control was also included in our study. A review of the cases of these 16 patients found that N. transvalensis caused infection in 10 patients and colonization in two patients. Six (75%) of eight patients with primary pulmonary or disseminated N. transvalensis infections had an underlying immunologic disorder or were receiving immunosuppressive therapy; three patients with disseminated infection died. All nine infected patients for whom specific antimicrobial therapy was prescribed received trimethoprim-sulfamethoxazole. Results of in vitro antimicrobial susceptibility tests of 11 N. transvalensis isolates revealed increased antimicrobial resistance to amikacin and other drugs when compared with that of other Nocardia species. Severely immunocompromised patients are predisposed to N. transvalensis pneumonia or disseminated infection, and the lung may be the portal of entry.