The role of rapidly growing mycobacteria in the pathogenesis of pulmonary disease is being increasingly recognized; however, the clinical significance of these mycobacteria in patients with underlying malignancy has not been well studied. Over a 6-year period, 37 cancer patients with rapidly growing mycobacteria isolated from respiratory specimens were identified at our center. Mycobacterium chelonae group was isolated in 24 cases and Mycobacterium fortuitum in 13 cases. Of the 24 cases with cultures yielding Mycobacterium chelonae group, eight met the study criteria for infection and were determined to be clinically significant, whereas only one of the Mycobacterium fortuitum isolates was determined to represent infection. An average of two antimicrobial agents were used for treatment, most commonly clarithromycin, ciprofloxacin, and trimethoprim/sulfamethoxazole. Although the isolation of rapidly growing mycobacteria represents colonization in most cases, these bacteria, especially the Mycobacterium chelonae group, may cause pulmonary disease in cancer patients. The clinical and radiological findings are usually non-specific in this population, and patients with respiratory cultures yielding rapidly growing mycobacteria should be assessed carefully to distinguish infection from colonization. Effective therapy can be provided with oral regimens that include at least two antibiotics to which the organism is susceptible.