Ceftriaxone was introduced into clinical practice in the USA in 1985 and was the first extended-spectrum (third-generation) cephalosporin approved for once-daily treatment of patients with Gram-positive or Gram-negative infections. Review of ceftriaxone activity is important given its continued use since the mid-1980s and reports of emerging resistance among all antimicrobial agent classes. We reviewed the activity of ceftriaxone and relevant comparative agents against five Gram-positive and 11 Gram-negative species for a 5-year period, 1996-2000, using data from The Surveillance Network (TSN) Database-USA. All MIC results were interpreted using NCCLS breakpoint criteria. Ceftriaxone resistance among isolates of Streptococcus pneumoniae (n=17219) remained essentially unchanged over the 5 years studied and in fact was lower from 1998 to 2000 (5.0-5.1%) than in 1996 (6.3%) and 1997 (6.6%). Ceftriaxone resistance (range, 5.1-6.9%) among viridans group streptococci (n=6621) varied by <2% from 1997 to 2000. Beta-lactam-resistant Streptococcus pyogenes (n=935) and group B beta-haemolytic streptococci (n=2267) were not identified in any year. Among methicillin-susceptible Staphylococcus aureus (n=39 284) ceftriaxone resistance was 0.1-0.3% per year from 1996 to 2000. Ceftriaxone resistance among Escherichia coli (n=472407; range, 0.2-0.4%), Klebsiella oxytoca (n=16231; range, 3.5-4.8%), Klebsiella pneumoniae (n=117754; range, 1.9-2.6%), Proteus mirabilis (n=67692; range, 0.2-0.3%), Morganella morganii (n=11251; range, 0.3-2.1%) and Serratia marcescens (n=26519; range, 1.6-3.8%) was low and consistent from 1996 to 2000. Resistance to ceftriaxone among Enterobacter cloacae (n=48114; range, 21.7-23.9%) was relatively high, compared with other Enterobacteriaceae, but unchanged from 1996 to 2000. Rates of resistance to ceftriaxone among Acinetobacter spp. (n=20813) increased from 24.8% in 1996 to 45.1% in 2000. All Haemophilus influenzae (n=7911) and Neisseria gonorrhoeae (n=218) were susceptible to ceftriaxone, as were 99.7% of Moraxella catarrhalis (n=312) tested in 1996 and 1997. In summary, ceftriaxone has retained its potent activity against the most commonly encountered Gram-positive and Gram-negative human pathogens despite widespread and ongoing clinical use for more than 15 years.