The objective of this article is to analyze the key factors that influence the effectiveness of an International Framework Agreement (IFA). Effectiveness is analyzed in terms of compliance of local labor management practices with the commitments made in the IFA. We regard negotiation as a process, composed of three phases (pre-negotiation, negotiation stricto sensu, post-negotiation) and embedded in a context. We develop an analytical model, based on Process Studies, highlighting the influence on IFA effectiveness of the positions, behaviors and interactions of the protagonists in the negotiation and application of this IFA. We detail the negotiation processes of four IFAs, concluded in the years 2010, by two French multinational corporations (MNCs) and two Global Union Federations (GUFs). These IFAs address labor management issues (occupational health and safety, gender equality, sustainable employment). This research is based on document analysis, observations and 38 interviews with international, European, national and local trade unionists, and members of the top management (TM) of these MNCs. It pays particular attention to the pre-negotiation phase and highlights the interactions between managerial and trade union actors throughout the negotiation process. We show that the position of the MNC top management (“social” or “managerial”) is a decisive factor in the progress of the IFA negotiation, in its outcome (“substantive” agreement) and its effectiveness. The “qualitative” position of the GUF may be a major element in the progress of the negotiation (choice of the IFA theme) and its outcome (provisions on sensitive issues). Finally, the mobilization of local unions, supported by the GUF, is essential to the effectiveness of an IFA. We reveal learning processes and IFA and International Collective Bargaining specificities.