OBJECTIVES: The usability of clinical information systems (CISs) is known to be an essential consideration in ensuring patient safety as well as integrating clinical flow. This study aimed to determine how usability and safety guidelines of CIS consider clinical workflow through a systematic review in terms of the target systems, methodology, and guideline components of relevant articles. METHODS: A literature search was conducted for articles published from 2000 to 2015 in PubMed, Cochrane, EMBASE, Web of Science, and CINAHL. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement method was employed. Articles containing recommendations, principles, and evaluation items for CIS usability and safety were included. The selected articles were classified according to article type, methodology, and target systems. Taking clinical workflow into consideration, the components of guidelines were extracted and classified. RESULTS: A total of 7,401 articles were identified by keyword search. From the 76 articles remaining after abstract screening, 15 were selected through full-text review. Literature review (n = 7) was the most common methodology, followed by expert opinions (n = 6). Computerized physician order entry (n = 6) was the most frequent system. Four articles considered the entire process of clinical tasks, and two articles considered the principles of the entire process of user interface affecting clinical workflow. Only two articles performed heuristic evaluations of CISs. CONCLUSIONS: The usability and safety guidelines of CISs need improvement in guideline development methodology and with consideration of clinical workflow.