Background: While chemotherapy is an effective modality for the treatment of patients with cancer, it is a complex, multidisciplinary, and error-prone process. Paper-based protocols are commonly applied in chemotherapy; however, they fail to eliminate the complexity of this process. Therefore, a new guideline-based workflow software (GWS) system is needed to improve the workflow and quality of chemotherapy process. Methods: Planning was initiated 11 months before the system implementation and it involved a multidisciplinary group to analyze the current chemotherapy workflow and protocols for identifying the workflow components, analyzing paper-based protocols, developing computer-based protocols, and designing of systems based on an object-oriented analysis. To implement the GWS, we applied a system based on Python programming language and SQL language. Results: The conceptual model was developed based on need assessments and chemotherapy steps. A minimum dataset was developed for the electronic health records. We established examination forms for the patient management system (PMS), as well as specific standard forms for chemotherapy ordering, prescription verification and administration templates. Finally, developed GWS system consisted of a PMS, computerized provider order entry (CPOE), prescription verification system (PVS), and nursing administration system (NAS). Conclusions: A PMS, a PVS, a NAS, and a protocol-based clinical decision support system were integrated into the CPOE system to improve the chemotherapy process. Elimination of iterations and unnecessary steps in old chemotherapy workflow, increase of patient safety, improvement of communication and coordination between healthcare providers, and use of updated evidence-based medicine in direct chemotherapy orders justify the integration of GWS in the cancer care settings.