We discuss some important management issues of the Human Biomonitoring Initiative (HBM4EU) from the perspective of the Coordinator that may be valuable for the design and management of similar projects. As a large-scale international collaborative project, HBM4EU comprised 118 institutions from 30 countries and the European Environment Agency and had a budget of about €74 million. It has set up an innovative cooperative network of national and EU authorities and scientific institutions at the science-policy interface. A project of this scale raises major management challenges and requires transparent, efficient, and well-organized administrative and scientific steering structures. We present four major points: First, prior to the beginning of the project, the Consortium Agreement needs to be well elaborated to prevent conflicts during the project lifetime. Second, a strong role for national and EU policy-making authorities in the administrative governance structure enhances the interest of recipients of project results. Third, large-scale international collaborative projects need an elaborate and well-financed scientific governance structure. Fourth, a differentiation of funding rates among project activities threatens to create conflicts. HBM4EU provides a prototype for EU funded large-scale projects targeting future policies for realizing the Green Deal and Zero Pollution Ambition in the field of chemicals, health, and environment.