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Presented here are two cases of multidrug-resistant Nocardia farcinica infection that occurred in immunocompromised patients. One of the patients developed the infection despite being on trimethoprim/sulfamethoxazole prophylaxis for Pneumocystis jiroveci. These cases demonstrate the propensity of Nocardia spp. to cause disseminated disease and to develop resistance to multiple antimicrobial agents used in the initial treatment of serious Nocardia infection. These factors lead to the conclusion that empiric monotherapy with trimethoprim/sulfamethoxazole may not be sufficient. Treatment with a combination regimen of imipenem and amikacin may be a more promising initial therapy.