To examine the resistance rates and epidemiology of Streptococcus pneumoniae in Brooklyn, New York, isolates were collected during two boroughwide surveillance periods in 1997 and 1999. Of 138 isolates, 67% were susceptible to penicillin and 34% to ciprofloxacin. Susceptibility rates to ciprofloxacin decreased dramatically from 1997 to 1999 (47% to 16%, p=0.0003). Five isolates (3.6%) were resistant to levofloxacin. Western Brooklyn had lower rates of susceptibility to penicillin compared with eastern neighborhoods. More isolates in the eastern neighborhoods belonged to the Spanish/French 9/14 clone, and isolates in the western neighborhoods tended to belong to the Spanish/USA 23F clone. Residents of the western neighborhoods were more likely to be white and elderly and less likely to be receiving Medicaid or public assistance, characteristics associated with increased health-care and antibiotic use. Brooklyn residents appear to be at high risk for fluoroquinolone-resistant S. pneumoniae. Our results underscore the need for vigilant regional surveillance.