BACKGROUND: Around one-third of the world's 2.8 million neonatal deaths are caused by infections. Most of these deaths are preventable, but occur due to delays in care-seeking, and access to effective antibiotic treatment with supportive care. Understanding variation in health system bottlenecks to scale-up of case management of neonatal infections and identifying solutions is essential to reduce mortality, and also morbidity. METHODS: A standardised bottleneck analysis tool was applied in 12 countries in Africa and Asia as part of the development of the Every Newborn Action Plan. Country workshops involved technical experts to complete a survey tool, to grade health system "bottlenecks" hindering scale up of maternal-newborn intervention packages. Quantitative and qualitative methods were used to analyse the data, combined with literature review, to present priority bottlenecks and synthesise actions to improve case management of newborn infections. RESULTS: For neonatal infections, the health system building blocks most frequently graded as major or significant bottlenecks, irrespective of mortality context and geographical region, were health workforce (11 out of 12 countries), and community ownership and partnership (11 out of 12 countries). Lack of data to inform decision making, and limited funding to increase access to quality neonatal care were also major challenges. CONCLUSIONS: Rapid recognition of possible serious bacterial infection and access to care is essential. Inpatient hospital care remains the first line of treatment for neonatal infections. In situations where referral is not possible, the use of simplified antibiotic regimens for outpatient management for non-critically ill young infants has recently been reported in large clinical trials; WHO is developing a guideline to treat this group of young infants. Improving quality of care through more investment in the health workforce at all levels of care is critical, in addition to ensuring development and dissemination of national guidelines. Improved information systems are needed to track coverage and adequately manage drug supply logistics for improved health outcomes. It is important to increase community ownership and partnership, for example through involvement of community groups.