Mycobacteriosis is a significant disease of companion and wild birds which causes emaciation and widely distributed lesions, as well as being a potential zoonosis. Its primary aetiological agents in birds are Mycobacterium avium subsp. avium and the fastidious Mycobacterium genavense. This study monitored the therapy of birds naturally infected with Mycobacterium genavense to gain understanding of its effectiveness and the interrelation of co-infections with the disease course and pharmacotherapy. Five Atlantic canaries (Serinus canaria) and one Bengalese finch (Lonchura striata) with tentative diagnoses of mycobacteriosis resulting from M. genavense infection were treated twice daily with clarithromycin at 40 mg/kg, ethambutol at 30 mg/kg, and moxifloxacin at 10 mg/kg for 6 months. Two canaries were also found to be carriers of Cryptosporidium galli. Mycobacteria in faecal samples of all birds were investigated by bacterioscopy and quantitative PCR. Molecular tests yielded positive results for up to four months after treatment initiation for M. genavense and Cryptosporidium, but microscopy failed to detect the latter after four weeks in specimens from one canary. Co-infections with polyomavirus (in all birds) and circovirus and bornavirus (in canaries) were diagnosed. Two birds died during treatment and one was euthanised because of other disease, 1 month after treatment completion. Three canaries were in relatively good health a year after treatment. Canary circovirus and polyomavirus co-infection may suppress the immune system and this may facilitate the development of mycobacteriosis. The set of drugs used led to the complete cure of mycobacteriosis in three canaries. In one bird the disease returned. Clarithromycin was the active drug against C. galli. Molecular methods serve well to monitor mycobacteriosis therapy and identify M. genavense and C. galli carriage.