The purpose of this study was to compare the in vitro activity of 27 antimicrobial compounds against 698 clinical Streptococcus pneumoniae isolates collected at 20 European university hospitals. Of the isolates tested, 21.3% were intermediately resistant to penicillin and 6.2% displayed high-level resistance to penicillin. Resistance to different antibiotics was more common among intermediately penicillin-resistant strains than among penicillin-susceptible strains and was most common among high-level penicillin-resistant organisms. The results of the current surveillance study confirm the ongoing trend among European clinical pneumococcal isolates of decreased sensitivity to various antibiotics.