Retis-Risk is a comprehensive framework recently developed for the assessment and management of the seismic resilience of interurban roadway networks. In this paper, this framework is applied for the road network of the prefecture of Western Macedonia in Greece. Refined data concerning real traffic conditions and network topology were collected and a detailed network mapping was performed in GIS. Utilizing an ad-hoc developed software for implementing the holistic methodology, the as-built road network was assessed and the network components with the highest vulnerability and consequence were identified. To improve the loss assessment reliability, bridge-specific fragility curves were employed based on the refined FE modeling. Structural and traffic cost due to earthquake scenarios of different return period were then predicted. To identify effective loss mitigation measures, the whole process was repeated assuming two different pre-earthquake risk management strategies. The first one concerns a retrofit program tailored to selected (i.e., the most critical) network components, while the second one focuses on the beneficial effect of a better recovery planning. Results indicate the significant contribution of an effective risk management to the loss mitigation and network resilience improvement. Moreover, a sustainable health monitoring system was installed on Polymylos bridge to ensure satellite data transmission during an earthquake event to update the postearthquake recovery model, nearly in real time, with the measured spectral acceleration of the superstructure. The results indicate that the road network is adequately resilient, primarily due to its newly constructed infrastructure and its compliance to modern seismic standards. However, it consists an interesting application case demonstrating the applicability of the methodology and the major potential benefits of a holistic resilience-based management for the case similar intercity highway networks.