The global community is beginning to address non-communicable diseases, but how to increase the accountability of multinational enterprises (MNEs) for the health impacts of their products and practices remains unclear. We examine the Organization for Economic Cooperation and Development's (OECD) efforts to do so through voluntary MNE guidelines. We developed a historical case study of how the OECD Guidelines for Multinational Enterprises were developed and revised from 1973 to 2000 through an analysis of publicly available archived OECD and tobacco industry documents. The first edition of the Guidelines was a purely economic instrument. Outside pressures and a desire to ward off more stringent regulatory efforts resulted in the addition over time of guidelines related to the environment, consumer interests, sustainable development and human rights. Despite their voluntary nature, the Guidelines can play a role in efforts to help balance the interests of MNEs and public health by providing a starting point for efforts to create binding provisions addressing MNEs' contributions to disease burden or disease reduction.