Although Ghana has a well-organized primary health care system, it lacks policies and guidelines for developing or providing emergency referral services. In 2012, an emergency referral pilot—the Sustainable Emergency Referral Care (SERC) initiative—was launched by the Ghana Health Service in collaboration with community stakeholders and health workers in one subdistrict of the Upper East Region where approximately 20,000 people reside. The pilot program was scaled up in 2013 to a 3-district (12-subdistrict) plausibility trial that served a population of approximately 184,000 over 2 years from 2013 to 2015. The SERC initiative was fielded as a component of a 6-year health systems strengthening and capacity-building project known as the Ghana Essential Health Intervention Program. Implementation research using mixed methods, including quantitative analysis of key process and health indicators over time in the 12 intervention subdistricts compared with comparison districts, a survey of health workers, and qualitative systems appraisal with community members, provided data on effectiveness of the system as well as operational challenges and potential solutions. Monitoring data show that community exposure to SERC was associated with an increased volume of emergency referrals, diminished reliance on primary care facilities not staffed or equipped to provide surgical care, and increased caseloads at facilities capable of providing appropriate acute care (i.e., district hospitals). Community members strongly endorsed the program and expressed appreciation for the service. Low rates of adherence to some care protocols were noted: referring facilities often failed to alert receiving facilities of incoming patients, not all patients transported were accompanied by a health worker, and receiving facilities commonly failed to provide patient outcome feedback to the referring facility. Yet in areas where SERC worked to bypass substandard points of care, overall facility-based maternal mortality as well as accident-related deaths decreased relative to levels observed in facilities located in comparison areas.