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OBJECTIVE: To design and evaluate new pharmacogenomic (PGx) clinical decision support (CDS) alerts, built to adhere to PGx CDS design principles developed through socio-technical approaches. MATERIALS AND METHODS: Based on previously identified design principles, we created 11 new PGx CDS alert designs and developed an interactive web application containing realistic clinical scenarios and user workflows that mimicked a real-world EHR system. We recruited General Internal Medicine and Cardiology clinicians from Northwestern Medicine and recorded their interactions with the original and new designs. We measured clinician response, satisfaction, speed, and confidence through questionnaires and analysis of the recordings. RESULTS: The study included 12 clinicians. Participants were significantly more satisfied (p=0.0000001), faster (p=0.009), and more confident (p<.05) with the new designs than the original ones. The study lacked statistical power to determine whether prescribing accuracy was improved, but participants were no less accurate, and clinical actions were more concordant with alert interactions (p=0.004) with the new designs. We found a significant learning curve associated with the original designs, which was eliminated with the new designs. DISCUSSION: This study successfully demonstrates that socio-technical and user-centered design techniques can improve PGx CDS alert designs. Best practices for PGx CDS design are limited in the literature, with few effectiveness studies available. These results can help guide future PGx CDS implementations to be more clinician friendly and less time-consuming. CONCLUSION: The results of this study support the PGx CDS design principles we proposed in previous work. As a next step, the new designs should be implemented in a live setting for further validation.