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Nowadays, healthcare service organizations have been using Design for Six Sigma (DFSS) for managing innovation to create new products, services and business processes. This paper is intended to demonstrate the effectiveness of DFSS on managing innovation in healthcare service organizations. The research is conducted on five leading US healthcare service organizations. Furthermore, roadmap for managing innovation is proposed. The result confirms that the DFSS strengthens two factors in managing innovation: (1) finding an innovative idea, (2) guiding and realizing an innovative idea. In addition, DFSS plays a critical role in shifting paradigm from subjective to objective judgment. Moreover, DFSS provides a platform for strategic critical measurement.