Background: The Strategy of the Integrated Management of Childhood Illness (IMCI) was introduced in Central Asia and Europe to address the absence of evidence-based guidelines, the misuse of antibiotics, polypharmacy and over-hospitalization of children. A study carried out in 16 countries analysed the status and strengths of as well as the barriers to IMCI implementation and investigated how different health systems affect the problems IMCI aims to address. Here we present findings in relation to IMCI's effects on the rational use of drugs, particularly the improved rational use of antibiotics in children, the mechanisms through which these were achieved as well as counteracting system factors. Methods: 220 key informants were interviewed ranging from 5 to 37 per country (median 12). Data was analysed for arising themes and peer-reviewed. Results: The implementation of IMCI led to improved prescribing patterns immediately after training of health workers according to key informants. IMCI provides standard treatment guidelines and an algorithmic diagnostic- and treatment-decision-tool for consistent decision-making. Doctors reported feeling empowered by the training to counsel parents and address their expectations and desire for invasive treatments and the use of multiple drugs. Improved prescribing patterns were not sustained over time but counteracted by factors such as: doctors prescribing antibiotics to create additional revenues or other benefits; aggressive marketing by pharmaceutical companies; parents pressuring doctors to prescribe antibiotics; and access to drugs without prescriptions. Conclusions: Future efforts to improve child health outcomes must include: (1) the continued support to improve health worker performance to enable them to adhere to evidence-based treatment guidelines, (2) patient and parent education, (3) improved reimbursement schemes and prescription regulations and their consistent enforcement and (4) the integration of point-of-care tests differentiating between viral and bacterial infection into standards of care. Pre-requisites will be sufficient remuneration of health workers, sound training, improved health literacy among parents, conducive laws and regulations and reimbursement systems with adequate checks and balances to ensure the best possible care.