Building on previous OECD Health Working Papers on the economics of patient safety, this paper firstly provides an update on the health burden, and financial and economic cost of unsafe care. It then summarises the evidence on the cost-effectiveness and return on investment of various programmes and interventions to improve the safety of care across all care settings. Globally, unsafe care results in over 3 million deaths each year with an estimated disease burden similar to that of HIV/AIDS. In developed countries, the direct cost of unsafe care on to health budgets approaches 13% of healthcare spending (about USD 606 Billion a year or just over 1% of the combined economic output of OECD countries). Using a willingness to pay approach, the full global economic cost is estimated at over USD 1 trillion a year. A human capital approach suggests that patient harm slows global economic growth by 0.7% a year. Improving patient safety requires a whole of system approach, with the value created by implementing and investing in mutually re-enforcing interventions within a policy framework that encompasses all health system strata. Most cost-effective are multi-modal approaches that align clinical, corporate, and professional risk across system silos.