Acinetobacter baumannii represents a cunning pathogen with multiple resistance genes. The authors report their experience with the treatment of two multiple drug-resistant A. baumannii clones. At least one positive culture was noted in 359 patients and, 323 had sufficient data for analysis. Of these, 42 patients were colonized leaving 281 antibiotic-treated infected patients. The average age was 48.1 ± 20.6 years (mean ± standard deviation), total body burn surface area involvement (TBSA) was 30.8 ± 25%. Inhalation injury was confirmed by bronchoscopy in 238 of 323 (74%) patients. The day to the first A. baumannii culture was 7.9 ± 8.9 and 6.5 ± 8.8 days for the colonized and infected patients, respectively. Survival to discharge was 95.4% for colonized patients and 77.1% for infected patients. A total of 1425 sputum cultures, 123 catheter cultures from 40 patients, 1130 blood cultures from 176 patients, and 1925 wound cultures were obtained from the 318 infected patients (14 cultures per patient). Imipenem-cilastatin was first used in 162 patients, ampicillin-sulbactam in 40 patients, and cephalosporin in 41 patients. Imipenem-cilastatin was combined with ampicillin-sulbactam in 18 patients. Imipenem-cilastatin eradicated A. baumannii in 27%, caused persistence in 55%, and failure in 20%. Ampicillin-sulbactam eradicated A. baumannii in 17%, caused persistence in 51%, and failure in 34%. Imipenem-cilastatin combined with ampicillin-sulbactam eradicated 23% of the A. baumannii, with 54% persisting, and 23% failing therapy. Nonparametric analysis of three sets of 34 matched patients treated with imipenem-cilastatin, ampicillin-sulbactam, or a cephalosporin showed little difference in treatment outcomes. More rapid fever resolution and fewer positive cultures were noted in the imipenem-cilastatin treated group; however, length of stay was not different.