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Background: The Ghana Health Service in collaboration with partner institutions implemented a five-year primary health systems strengthening program known as the Ghana Essential Health Intervention Program (GEHIP). GEHIP was a plausibility trial implemented in an impoverished region of northern Ghana around the World Health Organizations (WHO) six pillars combined with community engagement, leadership development and grassroots political support, the program organized a program of training and action focused on strategies for saving newborn lives and community-engaged emergency referral services. This paper analyzes the effect of the GEHIP program on child survival. Methods: Birth history data assembled from baseline and endline surveys are used to assess the hazard of child mortality in GEHIP treatment and comparison areas prior to and after the start of treatment. Difference-in-differences (DiD) methods are used to compare mortality change over time among children exposed to GEHIP relative to children in the comparison area over the same time period. Models test the hypothesis that a package of systems strengthening activities improved childhood survival. Models adjusted for the potentially confounding effects of baseline differentials, secular mortality trends, household characteristics such as relative wealth and parental educational attainment, and geographic accessibility of clinical care. Results: The GEHIP combination of health systems strengthening activities reduced neonatal mortality by approximately one half (HR = 0.52, 95% CI = 0.28,0.98, p = 0.045). There was a null incremental effect of GEHIP on mortality of post-neonate infants (from 1 to 12 months old) (HR = 0.72; 95% CI = 0.30,1.79; p = 0.480) and post-infants (from 1 year to 5 years old) -(HR = 1.02; 95% CI = 0.55–1.90; p = 0.940). Age-specific analyses show that impact was concentrated among neonates. However, effect ratios for post-infancy were inefficiently assessed owing to extensive survival history censoring for the later months of childhood. Children were observed only rarely for periods over 40 months of age. Conclusion: GEHIP results show that a comprehensive approach to newborn care is feasible, if care is augmented by community-based nurses. It supports the assertion that if appropriate mechanisms are put in place to enable the various pillars of the health system as espoused by WHO in rural impoverished settings where childhood mortality is high, it could lead to accelerated reductions in mortality thereby increasing survival of children. Policy implications of the pronounced neonatal effect of GEHIP merit national review for possible scale-up. [ABSTRACT FROM AUTHOR]