Marked improvement was observed in the condition of 6 cats with opportunistic mycobacterial infections during treatment with enrofloxacin, a fluoroquinolone antibiotic. Complete remission was achieved in 3 cats after 3 to 7 weeks of treatment. The other 3 cats were euthanatized after 1 to 2 weeks of treatment for reasons not related to the treatment. Lesions did not recur within the follow-up period, which ranged from 9 to 16 months. Treatment of opportunistic mycobacterial infection in cats is complicated because many mycobacteria are resistant to antituberculosis drugs, which also can be toxic to cats, and because results of susceptibility testing with other antimicrobials do not always correlate with clinical response. Often, neither satisfactory nor long-term response is observed in cats treated surgically or with the antibiotics currently recommended. These findings suggested that enrofloxacin is effective in the treatment of infections caused by Mycobacterium smegmatis and M fortuitum var fortuitum in cats.