Virtually all patients with cystic fibrosis (CF) die of respiratory failure resulting from chronic progressive pulmonary infections. Pseudomonas aeruginosa and Pseudomonas (Burkholderia) cepacia are the two major bacterial pathogens responsible for the pulmonary deterioration in these patients. Tobramycin has variable inhibitory effects on these organisms, but in many isolates this inhibition is increased in vitro by exposure to the diuretic, amiloride. Aerosolized amiloride has been shown to be of clinical benefit in CF. The basis for this synergy is unknown. To examine the possibility that amiloride-tobramycin synergy is mediated through a bacterial efflux mechanism mediated by a multidrug resistant (MDR) protein, we studied the inhibitory effect of verapamil, a known MDR inhibitor on the tobramycin MIC in P. aeruginosa and P. cepacia using standard MIC and synergy testing. Verapamil had no effect on the tobramycin MIC in P. aeruginosa but was able to act synergistically with tobramycin in reducing the tobramycin MIC markedly in all isolates of P. cepacia tested. This combination of drugs may be worth studying as a new treatment strategy for resistant P. cepacia infections.