Specimen handling is a critical patient safety issue. Problematic handling process, such as misidentification (of patients, surgical site, and specimen counts), specimen loss, or improper specimen preparation can lead to serious patient harms and lawsuits. Value stream map (VSM) is a tool used to find out non-value-added works, enhance the quality, and reduce the cost of the studied process. On the other hand, healthcare failure mode and effect analysis (HFMEA) is now frequently employed to avoid possible medication errors in healthcare process. Both of them have a goal similar to Six Sigma methodology for process improvement. This study proposes a model that integrates VSM and HFMEA into the framework, which mainly consists of define, measure, analyze, improve, and control (DMAIC), of Six Sigma. A Six Sigma project for improving the process of surgical specimen handling in a hospital was conducted to demonstrate the effectiveness of the proposed model.