A limited number of publications indicate that certain interferons (IFNs) may have a role in difficult-to-treat tuberculosis. We present a 48-year-old male diabetic patient who was referred to our department with the presumptive diagnosis of multidrug resistant tuberculosis. During the previous 8 months, he had been treated initially with a four-drug regimen (rifampicin, isoniazid, pyrazinamide, and ethambutol), which was later modified by the addition of streptomycin and ciprofloxacin, but his clinical condition had not improved and his sputum smear microscopy had remained positive to acid-fast bacilli. Cultured Mycobacterium tuberculosis from his sputum was sensitive to rifampicin and isoniazid. We administered IFN-alpha-2a at a low dose of 3 million IU intramuscularly weekly, in combination with isoniazid, rifampicin, ethambutol, and pyrazinamide. Two months after initiation of this therapy, sputum smears became negative, and a dramatic improvement in the patient's clinical and radiological findings occurred. During a 4-year follow-up, all consecutive sputum cultures remain negative. This case provides additional confirmation that certain IFNs could, potentially, be useful as therapeutic adjuncts for selected cases of non-responding tuberculosis and, therefore, merit further consideration.