Abstract Purpose To map the level of clinical practice compatibility with a radiation oncology information system (ROIS) through a workflow- and clinical process-based method aimed at optimizing the safety, efficacy, and efficiency of patient care; to improve the understanding of the critical relationship between the clinical practice and ROIS. Methods and materials Clinic-specific workflow and infrastructure were classified into clinical processes, information management, and technological innovation integration. Clinical information systems-information technology infrastructure and process maps were generated by a team of experts, representing clinical constituents. These maps served as the basis for evaluating connectivity and process flow and to guide the development of a quantitative survey where all clinical tasks and subprocesses were ranked according to importance in patient care and scored by the team of experts for performance. Process maps and survey output were used to measure ROIS compatibility with the practice and to guide practice improvement. Results Practice-specific process and infrastructure maps were generated. The developed survey was applied and results indicate a range of ROIS compatibility with clinical workflow and infrastructure. Survey results combined with experiential feedback provided specific prioritized guidance to improve both ROIS performance and clinic-specific processes and infrastructure. Conclusions This work provides a systematic and customizable tool to understand and evaluate clinical information and workflow and its compatibility with a given ROIS. The analysis provides insight into workflow improvements and information systems and information technology infrastructure limitations. Participating in such a process provides the entire team with a deeper understanding of the critical relationship between the clinical practice and the ROIS.