<jats:sec>
            <jats:title>Abstract</jats:title>
            <jats:p>Clinical decision support systems (CDSSs) have been developed to give guidance for referring physicians to make appropriate decisions at the point of care. The MIDAS study, a multicenter cluster randomized trial at four German university hospitals, was designed to evaluate the effectiveness of a CDSS for imaging referral (ESR iGuide) in routine clinical care. Based on our experience within the MIDAS study, we aim to describe the hurdles and difficulties, as well as the various insights gained, in the process of implementing a CDSS in a clinical and research setting. To successfully implement a CDSS for imaging requests, it is essential to monitor and address technical issues, adapt local workflows, define the scope and content, and prioritize user experience and acceptance.</jats:p>
          </jats:sec>
          <jats:sec>
            <jats:title>Critical relevance statement</jats:title>
            <jats:p>By identifying and addressing the various technical, content-related, and workflow challenges, this article gives valuable insights to facilitate future implementations of the ESR iGuide and similar clinical decision support systems CDSSs for imaging orders.</jats:p>
          </jats:sec>
          <jats:sec>
            <jats:title>Trial registration number</jats:title>
            <jats:p>Approval from the Medical Ethics Review Committee was obtained under protocol numbers 20-069 (Augsburg), B 238/21 (Kiel), 20-318 (Lübeck) and 2020-15125 (Mainz). The trial is registered in the ClinicalTrials.gov register under registration number NCT05490290.</jats:p>
          </jats:sec>
          <jats:sec>
            <jats:title>Key Points</jats:title>
            <jats:p>
              <jats:list list-type="bullet">
                <jats:list-item>
                  <jats:p>This manuscript reviews the challenges of implementing a clinical decision support system (CDSS) (ESR iGuide).</jats:p>
                </jats:list-item>
                <jats:list-item>
                  <jats:p>Clinical implementation of a CDSS for imaging requests requires monitoring and adjustments in technical issues, local workflow, scope and content, and attention to user experience and acceptance.</jats:p>
                </jats:list-item>
                <jats:list-item>
                  <jats:p>Our experience may equip stakeholders with the knowledge to proactively address these challenges.</jats:p>
                </jats:list-item>
              </jats:list>
            </jats:p>
          </jats:sec>
          <jats:sec>
            <jats:title>Graphical Abstract</jats:title>
          </jats:sec>