Pakistan is one of the four countries in the world where polio eradication has not been achieved, despite an unprecedented inflow of resources dedicated to the programme over the last 15 years. The objective of this case study is to analyse the impact of Pakistan’s Polio Eradication Initiative (PEI) on health systems in Pakistan and to document the impact of the health system on polio eradication. Qualitative methods were used for the study. By and large, the impact of the PEI on health systems in Pakistan was found to be positive, as evidenced by a decline in poliovirus transmission. The programme can also be credited with establishing a sensitive nationwide disease surveillance system, building capacity for door-to-door outreach, and achieving the largest-ever funding allocations for a disease-specific programme in the country. The PEI’s negative effects include the time implications of organizing and implementing Supplementary Immunization Activities (SIAs) and reported abuse of the mode of payment used to conduct SIAs. The failure to achieve the polio eradication goal stems from weaknesses in Pakistan’s health systems and the country’s geo-political, security and broader governance challenges. Salient considerations include severe conflict-related limitations in reaching children in the tribal areas of the country, along with organizational, managerial and operational problems in achieving sufficient coverage, even in accessible areas. In many ways, the PEI has exposed critical weaknesses in Pakistan’s health system and its inability to deliver on targets, even when resource availability is not an issue.