It is well known that in vitro the combination of carbenicillin, ticarcillin, or other antipseudomonal penicillins with gentamicin, tobramycin, or other aminoglycoside antibiotics results in the inactivation of the antibacterial activity of the aminoglycoside. To assess the influence of the in vivo interaction of tobramycin and ticarcillin on experimental nephrotoxicity, male Fischer 344 rats were given either tobramycin alone (120 mg/kg per day), tobramycin (120 mg/kg per day) and ticarcillin (250 mg/kg per day) concomitantly, or the combination of these drugs at the same doses that had been preincubated for 24 h and at the time of delivery contained but 63 and 25%, respectively, of the initial concentrations of tobramycin and ticarcillin as measured by conventional analytical procedures. Initial experiments were conducted to determine the concentrations of the antibiotics in serum achieved after administration of each test solution. After a single dose of the test solution, ticarcillin concentrations in serum were higher and more prolonged in rats given tobramycin plus ticarcillin than in rats given ticarcillin alone. After 7 days of exposure to the test solutions, inulin clearance in animals given tobramycin alone was 0.15 +/- 0.1 (mean +/- 2 standard errors) ml/min per 100 g of body weight as compared with 0.53 +/- 0.1 in rats given tobramycin and ticarcillin concomitantly, 0.59 +/- 0.1 in animals given the partially inactivated tobramycin-ticarcillin mixture, and 0.79 +/- 0.1 in control rats. Although there was some improvement in inulin clearance in the group containing tobramycin alone, the three treatment groups maintained the same rank relationship in inulin clearance through 14 days of treatment. Real histology confirmed the attenuation of tubular injury in animals given tobramycin and ticarcillin concomitantly. There was no evidence of toxicity from the presumed inactivation complexes of tobramycin-ticarcillin. These results document an in vivo protective effect of ticarcillin on experimental tobramycin nephrotoxicity.