The use of rifampin combined with other antimicrobial agents for the treatment of 40 serious bacterial infections against which other treatment regimens had failed was reviewed. Seven of 17 staphylococcal infections (16 due to Staphylococcus aureus and one due to Staphylococcusepidermidis) were cured, as were 16 of 23 infections caused by gram-negative bacilli. In vitro tests of interaction between rifampin and other antibiotics produced variable results. However, eight rifampin-resistant strains (six of S. aureus, one of Pseudomonas aeruginosa, and one of Proteus mirabilis) emerged during combination therapy in seven patients; the drugs involved were rifampin plus vancomycin in three instances, rifampin plus gentamicin in two, rifampin plus colistin in one, and rifampin plus pristinamycin in one. Thus, while rifampin produced a dramatic beneficial effect in some patients with serious bacterial infections, the emergence of resistant strains, even with dual drug therapy, was identified as a potential problem.