Pseudomonas aeruginosa pneumonia is associated with high mortality despite appropriate systemic antibacterial therapy. To examine the effects of aerosolized tobramycin on experimental P. aeruginosa pneumonia, guinea pigs were assigned to two main groups: a study group, in which P. aeruginosa was instilled into the tracheal lumen, and a control group, in which normal saline was instilled. Each group was then subdivided according to treatment: normal saline or tobramycin by intramuscular injection, normal saline or tobramycin by aerosol, or normal saline or tobramycin via both aerosol and intramuscular injection. Compared with either intramuscular or aerosolized tobramycin, the combination of aerosol plus intramuscular tobramycin achieved slightly higher survival, total eradication of P. aeruginosa from lungs, and a significant further reduction of lung inflammatory changes. Adding aerosolized tobramycin to systemic tobramycin in the treatment of experimental P. aeruginosa pneumonia enhanced eradication of P. aeruginosa and mitigated pulmonary inflammatory changes.