Treatment of infections in the intensive care unit (ICU) represents a great challenge, especially those caused by Gram-negative organisms. Rapid introduction of appropriate antimicrobial therapy is crucial to reduce mortality; resistance rates in the ICU can be elevated due to antimicrobial selection pressure. We evaluated the antimicrobial susceptibility patterns of Gram-negative bacteria isolated from patients hospitalized in ICUs (ICU patients). The isolates were consecutively collected as part of the SENTRY Antimicrobial Surveillance Program from January 2009 to December 2011 and tested for susceptibility to multiple antimicrobial agents at a central laboratory by reference broth microdilution methods. Antimicrobial susceptibility results for 5989 bacterial isolates from ICU patients (3445 from the United States [USA] and 2544 from Europe [EU]) were analyzed and compared to those of 17,244 organisms from non-ICU patients (9271 from USA and 7973 from EU). Escherichia coli, Klebsiella spp., and Pseudomonas aeruginosa were the most frequently isolated organisms from ICU patients, followed by Enterobacter spp., Serratia spp., Haemophilus influenzae, Acinetobacter spp., and Proteus mirabilis. Susceptibility rates were generally lower among ICU isolates compared to non-ICU organisms. E. coli isolates from ICU patients exhibited elevated extended-spectrum β-lactamase (ESBL)-phenotype rates (13.7% in USA and 16.6% in EU); furthermore, only amikacin (90.5-94.8% susceptibility), colistin (99.8-100.0% inhibited at ≤2 μg/mL), imipenem (95.5-96.0%), meropenem (95.4-95.8%), and tigecycline (96.3-98.0%) exhibited good activity against Klebsiella spp. ESBL-phenotype rates have increased among both E. coli and Klebsiella spp. from ICU patients in the USA and in Europe, with the most noticeable increase among Klebsiella spp. from Europe (from 27.5% in 2009 to 41.8% in 2011; P = 0.015 and odds ratio = 0.89 [95% confidence interval, 1.13-3.18]). Meropenem susceptibility among Klebsiella spp. improved slightly in the USA but decreased markedly in Europe from 100.0% in 2009 to 89.7% in 2011. Only colistin (99.4% susceptible) and amikacin (97.3% in USA and 84.9% in EU) exhibited good activity against P. aeruginosa strains from ICU patients. The greatest differences in susceptibility rates between P. aeruginosa strains from ICU and non-ICU patients were observed for the anti-pseudomonal β-lactams, such as ceftazidime, meropenem, and piperacillin/tazobactam. The results of this study (101 medical centers) highlight major antimicrobial coverage problems and trends in antimicrobial resistance for USA and EU ICU patient isolates.