We report on two cases of pneumococcal infection caused by strains demonstrating high-level cefotaxime resistance (minimal inhibitory concentration, 4 microg/mL). One patient had acute community-acquired meningitis with bacteraemia and the other had bacteraemia probably as a result of nosocomial pneumonia. Both patients died despite treatment with third generation cephalosporins. This is the first report from Hong Kong of infection with Streptococcus pneumoniae with high-level cefotaxime resistance that resulted in death. The emergence of high-level resistance to third-generation cephalosporins will result in treatment failure when these agents or penicillin are used alone, especially in cases of severe infection, such as meningitis, in which drug penetration of the blood-brain barrier is critical. The treatment of severe infections due to these isolates is problematic. Indiscriminate use of life-saving third-generation cephalosporins as out-patient treatment of minor infections or as first-line therapy for uncomplicated community-acquired infections in the hospital and in the community should be discouraged.