Aim: The status of outpatient irrational prescription drug use before and after pharmacist interventions in 6 large scale hospitals was investigated to determine the underlying reasons and to promote rational clinical drug use. Materials and methods: The 5-step DMAIC method (define, measure, analyze, improve, control) in Six Sigma management was utilized to investigate irrational drug use in prescriptions. The statistical software package SAS9.1.3 was adopted to analyze the results, determine possible reasons that could lead to irrational drug use, and then intervene accordingly. Statistics before and after the intervention were compared to analyze the function and effect of Six Sigma management in rational drug use via pharmacist intervention. Results: Irrational drug use rates (defect rates) before and after the intervention were 8.56% and 4.46% (P < 0.001), the Z value increased from 2.82 to 3.01, and the differences were significant. Conclusion: Six Sigma management will be able to computerize and refine hospital management, thereby ultimately improving service quality.