OBJECTIVE: To examine temporal trends of adverse drug reactions (ADRs) associated with trimethoprim-sulfamethoxazole (TMP-SMX) use in children. METHODS: We performed a retrospective observational study to characterize TMP-SMX ADRs in children between 2000 and 2009. We completed a chart review at our institution by identifying children diagnosed with TMP-SMX ADRs. To compare local trends to comparable institutions, we estimated the frequency of hospitalizations for TMP-SMX ADRs at 25 tertiary pediatric hospitals utilizing the Pediatric Health Information System database. To determine whether changes in outpatient prescribing rates occurred, we used the National Ambulatory Medical Care Survey/National Hospital Ambulatory Medical Care Survey. RESULTS: At our institution, 109 children were diagnosed with a TMP-SMX ADR (5 cases from 2000 to 2004 as compared with 104 cases from 2005 to 2009). Fifty-eight percent had been treated for a skin and soft tissue infection (SSTI). A similar trend was observed nationally, where the incidence of TMP-SMX ADRs more than doubled from 2004 to 2009 at comparable pediatric hospitals (P < .001). Although national outpatient data revealed no change in overall TMP-SMX prescribing, the percentage of children prescribed TMP-SMX for SSTI sharply increased during the study period (0%-2% [2000-2004]; 9%-17% [2005-2009]). CONCLUSIONS: The majority of TMP-SMX ADRs at our institution occurred in conjunction with SSTI treatment. TMP-SMX ADRs have occurred more frequently coincident with increased prescribing for SSTI. Increased usage alone may explain the increasing trend of TMP-SMX ADRs in children; however drug-disease interaction may play a role and requires further investigation.