Streptococcus pneumoniae isolates (6,958) were collected from patients at 163 U.S. medical centers during 2009 through 2012. Isolates were evaluated for multidrug resistance (MDR) to penicillin, ceftriaxone, erythromycin, tetracycline, trimethoprim-sulfamethoxazole, and levofloxacin. Ceftaroline was 16-fold more potent than ceftriaxone (MIC50/MIC90, ≤0.25/2 μg/ml) against all isolates. For MDR isolates (35.2% of tested strains), ceftaroline (MIC50/MIC90, 0.06/0.25 μg/ml; 100.0% susceptible) was the most active agent tested, being 8-fold more potent than ceftriaxone (MIC50/MIC90, 0.5/2 μg/ml) and 16-fold more potent than penicillin (MIC50/MIC90, 1/4 μg/ml).