The association between trimethoprim-sulfamethoxazole use and resistance among the major respiratory tract pathogens was investigated by comparing regional consumption of the drug to regional resistance in the following year in 21 central hospital districts in Finland. A total of 23,530 Streptococcus pneumoniae isolates, 28,320 Haemophilus influenzae isolates, and 14,138 Moraxella catarrhalis isolates were tested for trimethoprim-sulfamethoxazole susceptibility during the study period (1998-2004). Among the S. pneumoniae isolates, a statistically significant connection was found between regional consumption and resistance. No statistically significant connection was found between regional trimethoprim-sulfamethoxazole use and resistance among H. influenzae and M. catarrhalis isolates. According to our results, it seems that only in pneumococci can the development of trimethoprim-sulfamethoxazole resistance be influenced by restricting its use. However, trimethoprim-sulfamethoxazole remains an important antimicrobial agent because of its reasonable price. Hence, resistance to trimethoprim-sulfamethoxazole among these pathogens needs continuous monitoring.