A laboratory-based surveillance study of adult invasive pneumococcal disease was conducted in North-Rhine Westphalia, Germany's most populous federal state, with approximately 18 million inhabitants. Invasive isolates (n = 519) were obtained between 2003 and 2006, before the general recommendation for vaccination of German children <2 years with the pneumococcal conjugate vaccine was issued at the end of July 2006. Penicillin G resistance was observed in 5% of meningitis cases. In the non-meningitis group, only intermediately resistant strains were detected (0.4%). Intermediate resistance to cefotaxime occurred both in meningitis cases (1.7%) and non-meningitis cases (0.4%). Non-susceptibility rates (intermediate resistance and resistance) were 16.2% for macrolides, 10.9% for trimethoprim-sulphamethoxazole, 5.0% for tetracycline, 3.9% for clindamycin, and 0.4% for levofloxacin. All isolates were susceptible to amoxycillin (non-meningitis) and telithromycin. The leading serotypes were serotypes 14 (14.3%), 7F (9.4%), 3 (9.2%), 4 (8.7%) and 1 (8.1%). Serotype coverage for the seven-valent conjugate vaccine was 43.9%. For the ten-valent and 13-valent vaccines (in development), the coverages were 61.8% and 76.7%, respectively. The 23-valent polysaccharide vaccine had a coverage of 91.1%.