To monitor disease incidence and antibiotic resistance, effective, practical surveillance strategies are needed at the local level for drug-resistant Streptococcus pneumoniae (DRSP). Knox County, Tennessee, participates in three forms of DRSP surveillance: an active system sponsored by the Centers for Disease Control and Prevention (CDC; Atlanta, Georgia); a novel county-sponsored system; and conventional state-mandated reporting. Ascertainment of invasive S. pneumoniae infection cases by each system in 1998 was evaluated, and completeness of reporting, antibiotic resistance patterns, costs, and other attributes were compared. The county-sponsored system collects patient identifiers and drug susceptibility data directly from hospital laboratories, whereas the CDC-sponsored system performs medical chart abstractions and reference laboratory susceptibility testing. Similar numbers of invasive S. pneumoniae cases were detected by the county-sponsored (n = 127) and CDC-sponsored (n = 123) systems; these systems held >75% of all cases in common, and each system achieved >85% sensitivity. Conventional reporting contained 88% and 76% of the DRSP cases identified by the county- and CDC-sponsored systems, respectively, but did not capture infections produced by susceptible isolates. Both the county- and CDC-sponsored systems indicated that large proportions of isolates were resistant to penicillin and extended-spectrum cephalosporins. The county-sponsored DRSP surveillance system was inexpensive, simple to execute, and relevant to local needs.