From four southern European countries (Spain, Italy, Portugal, and Greece) 877 Streptococcus pneumoniae isolates were recovered from adult patients with respiratory tract infections between September 2000 and March 2001. The antimicrobial susceptibility to 11 antibiotics was determined in a central laboratory. Penicillin resistance was high in Greece (47.1%) and Spain (25.1%) but much lower in Portugal (7.9%) and Italy (4.8%). On the other hand, erythromycin resistance was high in Italy (38.5%) and Spain (36.2%) with no statistical difference with Greece (29.4%) but reaching significance (p <0.01) with Portugal (15.7%). Resistance to levofloxacin was low (1.5%) but present in Spanish and Italian isolates. Cefditoren, a new cephem antibiotic tested, was the most potent compound (MIC90 = 0.5 microg/ml) followed by levofloxacin and cefotaxime (MIC90 = 1 microg/ml). Given the high rates of penicillin and macrolide resistance reported, there is an evident need for new drugs and continued antimicrobial surveillance of S. pneumoniae.