Antibiotics are used for both group B streptococcal (GBS) prevention and treatment. Active population-based surveillance for invasive GBS disease was conducted in four states during 1996-2003. Of 3813 case-isolates, 91.0% (3471) were serotyped, 77.1% (2937) had susceptibility testing, and 46.6% (3471) had both. All were sensitive to penicillin, ampicillin, cefazolin, cefotaxime, and vancomycin. Clindamycin and erythromycin resistance was 12.7% and 25.6%, respectively, and associated with serotype V (P <.001). Clindamycin resistance increased from 10.5% to 15.0% (X 2 for trend 12.70; P <.001); inducible clindamycin resistance was associated with the erm genotype. Erythromycin resistance increased from 15.8% to 32.8% (X 2 for trend 55.46; P <.001). While GBS remains susceptible to beta-lactams, resistance to alternative agents such as erythromycin and clindamycin is an increasing concern.