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Background: Electronic decision-making support systems (CDSSs) can support clinicians to make evidence-based, rational clinical decisions about patient management and have been effectively implemented in high-income settings. Integrated Management of Childhood Illness (IMCI) uses clinical algorithms to provide guidelines for management of sick children in primary health care clinics and is widely implemented in low income countries. A CDSS based on IMCI (eIMCI) was developed in South Africa., Methods: We undertook a mixed methods study to prospectively explore experiences of implementation from the perspective of newly-trained eIMCI practitioners. eIMCI uptake was monitored throughout implementation. In-depth interviews (IDIs) were conducted with selected participants before and after training, after mentoring, and after 6 months implementation. Participants were then invited to participate in focus group discussions (FGDs) to provide further insights into barriers to eIMCI implementation., Results: We conducted 36 IDIs with 9 participants between October 2020 and May 2021, and three FGDs with 11 participants in October 2021. Most participants spoke positively about eIMCI reporting that it was well received in the clinics, was simple to use, and improved the quality of clinical assessments. However, uptake of eIMCI across participating clinics was poor. Challenges reported included lack of computer skills which made simple tasks, like logging in or entering patient details, time consuming. Technical support was provided, but was time consuming to access so that eIMCI was sometimes unavailable. Other challenges included heavy workloads, and the perception that eIMCI took longer and disrupted participant's work. Poor alignment between recording requirements of eIMCI and other clinic programmes increased participant's administrative workload. All these factors were a disincentive to eIMCI uptake, frequently leading participants to revert to paper IMCI which was quicker and where they felt more confident., Conclusion: Despite the potential of CDSSs to increase adherence to guidelines and improve clinical management and prescribing practices in resource constrained settings where clinical support is scarce, they have not been widely implemented. Careful attention should be paid to the work environment, work flow and skills of health workers prior to implementation, and ongoing health system support is required if health workers are to adopt these approaches (350)., (© 2023. The Author(s).)