We investigated the antimicrobial activity of piperacillin-tazobactam versus piperacillin-sulbactam against common nosocomial pathogens (n = 565) isolated from intensive care patients. For Gram-positive bacteria, antimicrobial susceptibilities to the two piperacillin-beta-lactamase inhibitor combinations were almost identical. For Gram-negative bacteria, piperacillin-tazobactam exhibited greater activity against Escherichia coli and Proteus vulgaris than piperacillin-sulbactam. Both combinations, however, were equally effective against the other Enterobacteriaceae and Pseudomonas aeruginosa isolates. Piperacillin-sulbactam exhibited better antimicrobial activity against Acinetobacter baumannii. Our findings might prove important for the appropriate choice of antibiotic therapy with beta-lactam-beta-lactamase inhibitor combinations.