The resurgence of tuberculosis is a major problem. Increasing multiple resistance to current drugs used for therapy, non-compliance to therapy or co-morbidity are challenging problems that do not allow use of standard therapy in all patients. Quinolones are claimed to be active drugs in TB infection. Moxifloxacin shows the highest intracellular concentration in vitro and in experimental animals, but long-term tolerability is unknown. Our aim was to observe in compliant patients, not eligible for standard therapy, the effect of 6 months of therapy with moxifloxacin, isoniazid and rifampin. Nineteen patients, a control group, were observed for the same period under therapy with streptomycin, pirazinamide, rifampin, isoniazid. The patients were affected by indolent miliary pattern and concomitant lymphoma or leukemia in 3 cases; rare nodular involvement with genitourinary diseases in 3 others; segmental to lobar involvement in 4 others with concomitant multidrug resistance, bone localization, hepatitis. The control group was more uniform and showed segmental to lobar nodular involvement with pleuritis in 3 patients, together with hepatitis in 3. Monthly checks of blood gas analysis, chest X-ray, functional testing, serum titers of antibodies against antigen 60, sputum slides and complete chemical analysis were performed. A follow-up visit was performed 1 month after therapy. Patients under moxifloxacin therapy experienced no toxicity, almost complete sterilization and remission of the disease. Sterilization was obtained in 15 days. Patients under standard therapy also had a good clinical outcome, although therapy was delayed in 3 cases because of increased transaminases within the first 15 days of therapy. Moxifloxacin seems to be well tolerated and combination therapy including moxifloxacin for TB seems to be as active as the standard therapy in patients with complex illness.