The effect of piperacillin administration on the dispositions of netilmicin and tobramycin was assessed in 12 chronic hemodialysis patients. Six subjects each received netilmicin (2 mg/kg) or tobramycin (2 mg/kg) alone and in combination with piperacillin (4 g every 12 h for four doses). Subjects also received a single dose of piperacillin (4 g) on a separate occasion. The serum concentration-versus-time profiles of netilmicin and tobramycin were bioexponential. The terminal elimination half-life (t( 1/2 β)) of tobramycin was markedly reduced (59.62 ± 25.18 [mean ± standard deviation] versus 24.71 ± 5.41 h) and total body clearance (CL(P)) was significantly increased in the presence of piperacillin (3.45 ± 1.61 versus 7.16 ± 1.64 ml/min). In contrast, the t( 1/2 β) (41.80 ± 13.24 versus 40.07 ± 10.37 h) and CL(P) (5.11 ± 2.15 versus 5.55 ± 2.32 ml/min) of netilmicin were not significantly altered when netilmicin was administered in combination with piperacillin. No change in the central or steady-state volume of distribution of netilmicin or tobramycin was observed. The disposition of piperacillin in hemodialysis patients was not altered in the presence of either aminoglycoside antibiotic. Although no adjustment in netilmicin dosing is required, tobramycin should be administered more frequently when given concomitantly with piperacillin to hemodialysis patients to avoid prolonged periods of subtherapeutic concentrations.