BackgroundClosing loops to complete diagnostic referrals remains a significant patient safety problem in most health systems, with 65%–73% failure rates and significant delays common despite years of improvement efforts, suggesting new approaches may be useful. Systems engineering (SE) methods increasingly are advocated in healthcare for their value in studying and redesigning complex processes.ObjectiveConduct a formative SE analysis of process logic, variation, reliability and failures for completing diagnostic referrals originating in two primary care practices serving different demographics, using dermatology as an illustrating use case.MethodsAn interdisciplinary team of clinicians, systems engineers, quality improvement specialists, and patient representatives collaborated to understand processes of initiating and completing diagnostic referrals. Cross-functional process maps were developed through iterative group interviews with an urban community-based health centre and a teaching practice within a large academic medical centre. Results were used to conduct an engineering process analysis, assess variation within and between practices, and identify common failure modes and potential solutions.ResultsProcesses to complete diagnostic referrals involve many sub-standard design constructs, with significant workflow variation between and within practices, statistical instability and special cause variation in completion rates and timeliness, and only 21% of all process activities estimated as value-add. Failure modes were similar between the two practices, with most process activities relying on low-reliability concepts (eg, reminders, workarounds, education and verification/inspection). Several opportunities were identified to incorporate higher reliability process constructs (eg, simplification, consolidation, standardisation, forcing functions, automation and opt-outs).ConclusionFrom a systems science perspective, diagnostic referral processes perform poorly in part because their fundamental designs are fraught with low-reliability characteristics and mental models, including formalised workaround and rework activities, suggesting a need for different approaches versus incremental improvement of existing processes. SE perspectives and methods offer new ways of thinking about patient safety problems, failures and potential solutions.