Complex socio-technical health information systems (HIS) issues can create new error risks. Therefore, we evaluated the management of HIS-related errors using the proposed human, organization, process, and technology-fit framework to identify the lessons learned. Qualitative case study methodology through observation, interview, and document analysis was conducted at a 1000-bed Japanese specialist teaching hospital. Effective management of HIS-related errors was attributable to many socio-technical factors including continuous improvement, safety culture, strong management and leadership, effective communication, preventive and corrective mechanisms, an incident reporting system, and closed feedback loops. Enablers of medication errors include system sophistication and process factors like workarounds, variance, clinical workload, slips and mistakes, and miscommunication. The case management effectiveness in handling the HIS-related errors can guide other clinical settings. The potential of HIS to minimize errors can be achieved through continual, systematic, and structured evaluation. The case study validated the applicability of the proposed evaluation framework that can be applied flexibly according to study contexts to inform HIS stakeholders in decision-making. The comprehensive and specific measures of the proposed framework and approach can be a useful guide for evaluating complex HIS-related errors. Leaner and fitter socio-technical components of HIS can yield safer system use.