Background: Substandard and falsified medicines promote antimicrobial resistance and undermine progress towards universal health coverage. We investigated the political and economic factors that incentivise and facilitate the production, trade and consumption of these products.Methods: We conducted in-depth case studies in China, Indonesia, Turkey and Romania. We reviewed academic papers and press reports, developing a preliminary coding structure and semi-structured questionnaires. We interviewed regulators, policy-makers, pharmaceutical manufacturers, physicians, pharmacists, patients and academics. Using critical interpretive synthesis, we developed an analytic framework to assess national risks for substandard and falsified medicines. We tested the framework against cases reported to the World Health Organization.Results: Substandard medicines are likely where aggressive cost-cutting displaces quality assurance, sometimes in response to public procurement policies. Falsified medicines are produced by those seeking to profit illegally from shortages of clinically indicated, cost-effective products, or from unmet consumer demand, sometimes for clinically unnecessary products. Supply shortages often result from market withdrawal, arbitrage and other legal measures taken by profit-driven pharmaceutical companies responding to low prices. Irrational demand can be driven by physician/provider incentives as well as by marketing by legitimate and illegal suppliers. Shortages, irrational demand and high prices push consumers outside of the regular supply chain, providing an easy entry point for falsifiers. The framework describing these interactions was able to explain cases reported to the WHO from high, middle and low income settings.Interpretation: Market incentives are as important as product regulation in influencing medicine quality. Unless quality is explicitly included in procurement policies, cost-containment measures can incentivise the production of substandard medicines. Meanwhile, industry's quest to maximise profit globally creates local shortages and irrational demand, providing opportunities for falsifiers. A system-wide analysis of incentives can flag risks and pinpoint actions to protect medicine quality, and global health.Funding Statement: This work was supported through grant funding from the Wellcome Trust (Grant number 209930_Z_17_Z) and Erasmus University (through the REI grant: WBS number 22070000.014.002).Declaration of Interests: In 2017, EP received consultancy fees from the World Health Organization for separate contributions to work on medicine quality. All other authors declare they have no conflict of interest.Ethics Approval Statement: The study plan was submitted to the Medical Ethics Committee of Erasmus University, Rotterdam, who granted a waiver (MEC-2018-016).