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Context The impact of clinical decision support systems (CDSS) on antimicrobial prescribing in ambulatory settings has not previously been evaluated. Objective To measure the added value of CDSS when coupled with a community intervention to reduce inappropriate prescribing of antimicrobial drugs for acute respiratory tract infections. Design, Participants and Setting Cluster randomized trial that included 407 460 inhabitants and 334 primary care clinicians in 12 rural communities in Utah and Idaho (6 with 1 shared characteristic and 6 with another), and a third group of 6 communities that served as nonstudy controls. The preintervention period was January to December 2001 and the postintervention period was January 2002 to September 2003. Acute respiratory tract infection diagnoses were classified into groups based on indication for antimicrobial use. Multilevel regression methods were applied to account for the clustered design. Intervention Six communities received a community intervention alone and 6 communities received community intervention plus CDSS that were targeted toward primary care clinicians. The CDSS comprised decision support tools on paper and a handheld computer to guide diagnosis and management of acute respiratory tract infection. Main Outcome Measure Community-wide antimicrobial usage was assessed using retail pharmacy data. Diagnosis-specific antimicrobial use was compared by chart review. Results Within CDSS communities, 71% of primary care clinicians participated in the use of CDSS. The prescribing rate decreased from 84.1 to 75.3 per 100 person-years in the CDSS arm vs 84.3 to 85.2 in community intervention alone, and remained stable in the other communities (P = .03). A total of 13 081 acute respiratory tract infection visits were abstracted. The relative decrease in antimicrobial prescribing for visits in the antibiotics “never-indicated” category during the post-intervention period was 32% in CDSS communities and 5% in community intervention-alone communities (P = .03). Use of macrolides decreased significantly in CDSS communities but not in community intervention–alone communities. Conclusion CDSS implemented in rural primary care settings reduced overall antimicrobial use and improved appropriateness of antimicrobial selection for acute respiratory tract infections. Trial Registration ClinicalTrials.gov Identifier: NCT00235703. [ABSTRACT FROM AUTHOR]