Rationally designed combinations of rifampicin (RAMP) and thiacetazone plus isonicotinic acid hydrazide and/or ethambutol are highly effective in the treatment of patients (including HIV-positive) infected with multiply resistant mycobacteria of the Mycobacterium avium complex (MAC). Clinical results are very promising. The high efficacy of these combinations is due to the synergistic potentiation of single-drug activities. As soon as rifabutin is marketed, it should replace RAMP in the combination treatment of patients with highly RAMP-resistant MAC bacteria.