Nosocomial pneumonia and acute peritonitis may be caused by a wide array of pathogens, and combination therapy is often recommended. We have previously shown that imipenem-cilastatin monotherapy was as efficacious as the combination of imipenem-cilastatin plus netilmicin in these two settings. The efficacy of imipenem-cilastatin is now compared to that of piperacillin-tazobactam as monotherapy in patients with nosocomial pneumonia or acute peritonitis. Three hundred seventy one patients with nosocomial pneumonia or peritonitis were randomly assigned to receive either imipenem-cilastatin (0.5 g four times a day) or piperacillin-tazobactam (4.5 g three times a day). Three hundred thirteen were assessable (154 with nosocomial pneumonia and 159 with peritonitis). For nosocomial pneumonia, clinical-failure rates in the piperacillin-tazobactam group (13 of 75 [17%]) and in the imipenem-cilastatin group (23 of 79 [29%]) were similar (P = 0.09), as were the numbers of deaths due to infection (6 in the imipenem-cilastatin group [8%], 7 in the piperacillin-tazobactam group [9%]) (P = 0.78). For acute peritonitis, clinical success rates were comparable (piperacillin-tazobactam, 72 of 76 [95%]; imipenem-cilastatin, 77 of 83 [93%]). For infections due to Pseudomonas aeruginosa, 45 patients had nosocomial pneumonia (21 in the piperacillin-tazobactam group and 24 in the imipenem-cilastatin group) and 10 had peritonitis (5 in each group). In the patients with nosocomial pneumonia, clinical failure was less frequent in the piperacillin-tazobactam group (2 of 21 [10%]) than in the imipenem-cilastatin [corrected] group (12 of 24 [50%]) (P = 0.004). Bacterial resistance to allocated regimen was the main cause of clinical failure (1 in the piperacillin-tazobactam group and 12 in the imipenem-cilastatin group). For the patients with peritonitis, no difference in clinical outcome was observed (five of five cured in each group). The overall frequencies of adverse events related to treatment in the two groups were similar (24 in the piperacillin-tazobactam group, 22 in the imipenem-cilastatin group). Diarrhea was significantly more frequent in the piperacillin-tazobactam group (10 of 24) than in the imipenem-cilastatin group (2 of 22). This study suggests that piperacillin-tazobactam monotherapy is at least as effective and safe as imipenem-cilastatin monotherapy in the treatment of nosocomial pneumonia or peritonitis. In P. aeruginosa pneumonia, piperacillin-tazobactam achieved a better clinical efficacy than imipenem-cilastatin, due to reduced development of microbiological resistance. Tolerance was comparable, with the exception of diarrhea, which was more frequent with piperacillin-tazobactam.