In Papua New Guinea, investment by the Global Fund to Fight AIDS, Tuberculosis and Malaria (the Global Fund) has played an important role in scaling up the response to HIV and tuberculosis (TB). As part of a series of case studies on how Global Fund-supported programmes interact with national health systems, we assessed the nature and extent of integration of the Global Fund portfolios within the national HIV and TB programmes, the integration of the HIV and TB programmes within the general health system, and system-wide effects of Global Fund support in Papua New Guinea. The study relied on a literature review and 30 interviews with key stakeholders using the Systemic Rapid Assessment Toolkit and thematic analysis. Global Fund-supported activities were found to be largely integrated, or at least coordinated, with the national HIV and TB programmes. However, this has reinforced the vertical nature of these programmes with respect to the general health system, with parallel systems established to meet the demands of programme scale-up and the performance-based nature of Global Fund investment in the weak health system context of Papua New Guinea. The more parallel functions include monitoring and evaluation, and procurement and supply chain systems, while human resources and infrastructure for service delivery are increasingly integrated at more local levels. Positive synergies of Global Fund support include engagement of civil-society partners, and a reliable supply of high-quality drugs which may have increased patient confidence in the health system. However, the severely limited and overburdened pool of human resources has been skewed towards the three diseases, both at management and service delivery levels. There is also concern surrounding the sustainability of the disease programmes, given their dependence on donors. Increasing Global Fund attention towards health system strengthening was viewed positively, but should acknowledge that system changes are slow, difficult to measure and require long-term support.