BACKGROUND: Regional trade agreements are major international policy instruments that shape macro-economic and political systems. There is widespread debate as to whether and how these agreements pose risks to public health. Here we perform a comprehensive systematic review of quantitative studies of the health impact of trade and investment agreements. We identified studies from searches in PubMed, Web of Science, EMBASE, and Global Health Online. Research articles were eligible for inclusion if they were quantitative studies of the health impacts of trade and investment agreements or policy. We systematically reviewed study findings, evaluated quality using the Quality Assessment Tool from the Effective Public Health Practice Project, and performed network citation analysis to study disciplinary siloes. RESULTS: Seventeen quantitative studies met our inclusion criteria. There was consistent evidence that implementing trade agreements was associated with increased consumption of processed foods and sugar-sweetened beverages. Granting import licenses for patented drugs was associated with increased access to pharmaceuticals. Implementing trade agreements and associated policies was also correlated with higher cardiovascular disease incidence and higher Body Mass Index (BMI), whilst correlations with tobacco consumption, under-five mortality, maternal mortality, and life expectancy were inconclusive. Overall, the quality of studies is weak or moderately weak, and co-citation analysis revealed a relative isolation of public health from economics. CONCLUSION: We identified limitations in existing studies which preclude definitive conclusions of the health impacts of regional trade and investment agreements. Few address unobserved confounding, and many possible consequences and mechanisms linking trade and investment agreements to health remain poorly understood. Results from our co-citation analysis suggest scope for greater interdisciplinary collaboration. Notwithstanding these limitations, our results find evidence that trade agreements pose some significant health risks. Health protections in trade and investment treaties may mitigate these impacts.