This was a one-group pretest-posttest study that developed a high-risk intravenous medication safety program by applying the Six Sigma technique to hospital nurses and measuring the pre- and post-effects. Participants were nurses with more than three years of experience in administering chemotherapy and highly concentrated intravenous electrolytes working at a university hospital in City D. Data analysis was performed using the Minitab 16 PC+ program; frequency, percentage, and 4-block matrix analyses were performed. In the definition stage, an improvement team was formed to proceed with the task, which was defined as a highrisk intravenous medication safety issue in ward nursing. In the analysis stage, a lack of high-risk intravenous medication safety education was identified. In the improvement stage, nurses were provided with high-risk intravenous medication safety education. Post-study knowledge scores increased significantly from 11.24 to 21.32, while performance scores improved from 36.61 to 68.45 (p < 0.05). This study identified and improved the problems in hospital organizational systems and presented a strategy for establishing a safety system in medical institutions and improving human factors. This ultimately enhanced the safety of high-risk intravenous administration.