Since 1989, 12 registration trials have been submitted to the US Food and Drug Administration to support the clinical efficacy of 8 antibacterial drugs for the treatment of nosocomial pneumonia. Six trials used noninferiority designs, whereas the others were equivalence trials or lacked a prespecified hypothesis. Patients with nosocomial pneumonia and ventilator-associated pneumonia were frequently enrolled in the same clinical trials. Enrolled patients were predominantly male and had mean Acute Physiology and Chronic Health Evaluation II scores of 12-18. The investigator's assessment of clinical response was the primary end point, which was usually measured 7-14 days after study drug completion. Clinical cure rates among the intent-to-treat population for nosocomial pneumonia and ventilator-associated pneumonia ranged from 37% to 69% and 25% to 58%, respectively. All-cause mortality ranged from 8% to 28%. Pseudomonas aeruginosa, Acinetobacter species, and methicillin-resistant Staphylococcus aureus were common bacterial pathogens. The design, implementation, and limitations of the clinical trials and implications for future clinical research are discussed.