The objective of this study was to explore and identify physical design correlates of safety and efficiency in emergency department (ED) operations. This study adopted an exploratory, multimeasure approach to (1) examine the interactions between ED operations and physical design at 4 sites and (2) identify domains of physical design decision-making that potentially influence efficiency and safety. Multidisciplinary gaming and semistructured interviews were conducted with stakeholders at each site. Study data suggest that 16 domains of physical design decisions influence safety, efficiency, or both. These include (1) entrance and patient waiting, (2) traffic management, (3) subwaiting or internal waiting areas, (4) triage, (5) examination/treatment area configuration, (6) examination/treatment area centralization versus decentralization, (7) examination/treatment room standardization, (8) adequate space, (9) nurse work space, (10) physician work space, (11) adjacencies and access, (12) equipment room, (13) psych room, (14) staff de-stressing room, (15) hallway width, and (16) results waiting area. Safety and efficiency from a physical environment perspective in ED design are mutually reinforcing concepts--enhancing efficiency bears positive implications for safety. Furthermore, safety and security emerged as correlated concepts, with security issues bearing implications for safety, thereby suggesting important associations between safety, security, and efficiency.