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Background Computerized clinical decision support systems (CDSS) have shown promising effectiveness in improving outpatient antibiotic prescribing. Methods We developed an intervention in the form of EPIC (Verona, WI, USA) order sets comprised of outpatient treatment pathways for 3 pediatric bacterial acute respiratory infections (ARIs) coupled with educational sessions. Four pediatric clinics were randomized into intervention and control arms over pre- and postimplementation study periods. In the intervention clinics, education was provided in between the 2 study periods and EPIC order sets became available at the beginning of the postimplementation period. The primary end point was the percentage of first-line antibiotic prescribing, and the secondary end points included antibiotic duration and antibiotic prescription modification within 14 days. Results A total of 2690 antibiotic prescriptions were included. During the pre-implementation phase, there was no difference in first-line antibiotic prescribing (74.9% vs 77.7%; P =.211) or antibiotic duration (9.69 ± 0.96 days vs 9.63 ± 1.07 days; P >.999) between the study arms. Following implementation, the intervention clinics had a higher percentage of first-line antibiotic prescribing (83.1% vs 77.7%; P =.024) and shorter antibiotic duration (9.28 ± 1.56 days vs 9.79 ± 0.75 days; P <.001) compared with the control clinics. The percentage of modified antibiotics was small in all clinics (1.1%–1.6%) and did not differ before and after the intervention (for all statistical comparisons, P ≤.354). Conclusions A computerized CDSS involving treatment pathways in the form of order sets coupled with educational sessions was associated with a higher percentage of first-line antibiotic prescribing and shorter antibiotic duration for the outpatient treatment of pediatric bacterial ARIs. [ABSTRACT FROM AUTHOR]