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Background The treatment of Nocardia species found in the sputum of cystic fibrosis patients is of unknown value. Methods We conducted a retrospective analysis of the impact of directed oral antibiotic therapy against Nocardia spp. isolated from the sputum of 17 cystic fibrosis patients over a 10-year period. Pulmonary Function Tests were used as the clinical indicator of the disease state and the data were analyzed by general linear mixed model statistics with univariate analysis. Results Pulmonary Function Test values of all patients studied showed no significant difference before, during, or after the antibiotic treatment period. Treatment groups did not differ from non-treatment groups. This held true for Forced Expiratory Volume over 1 s and Functional Vital Capacity analysis. In addition, individual patient analysis did not reveal any trends or outliers. Conclusions Oral antibiotic therapy of cystic fibrosis patients colonized with Nocardia does not appear to affect clinical outcome. This suggests that deferring therapy may be an acceptable alternative and justifies conducting a future placebo controlled trial. In addition, this study model may be useful in analyzing the effect of therapy on other rare and difficult organisms, such as fungi and mycobacteria in the cystic fibrosis population.