CHASE is a major community systems change initiative in 16 New York State (NYS) counties (8 intervention, 8 control) to reduce opioid overdose mortality by 40%. CHASE is a coordinated multi-system, multi-sector public health response to the opioid epidemic, directed by County Health Commissioners, and driven by robust community engagement and real-time learning based on data science and systems science. CHASE addresses structural barriers to decreasing opioid deaths by engaging underutilized county systems Spokes (e.g., jails, other justice settings, emergency departments (EDs), and other health and social service settings) will be linked to hubs which will include federally qualified health care clinics, primary care settings and addiction programs. CHASE will target gaps in the opioid prevention and treatment cascade by (1) expanding number of medications for opioid use disorder (MOUD) providers and addiction expertise; (2) identifying people at risk of opioid use disorder (OUD) using EBP screening, brief intervention and referral tools and linking and retaining them in MOUD using peer navigation; (3) scaling up overdose education and naloxone distribution (OEND) in community settings; (4) improving access to MOUD in jails and EDs, (5) deploying evidence-based prevention programs in schools, social media and other venues; and (6) scaling up prescription monitoring and prescription take-back programs. The study employs mixed methods to rigorously identify multi-level theory-driven factors that impede or facilitate the implementation and sustainability of CHASE in each county.