Introduction: Acute aortic dissection (AAD) is a rare but fatal condition where over-investigation and missed diagnosis are common. Our objectives were to derive a highly sensitive clinical risk score for AAD and perform pilot validation. Methods: We started with two independent systemic reviews to firstly identify clinical variables associated with AAD and secondly to determine reasons for missed diagnosis. We searched Medline, Embase and the Cochrane database (1968-July 2016). Two reviewers screened articles and extracted data. Agreement was measured by Kappa and study quality by the QUADAS-2 tool. Bivariate random-effects meta-analyses (Revman 5 and SAS 9.3) were performed. Due to sampling bias found in the systematic reviews a matched case control study confirming the strength and direction of predictor variables was performed. The cases (2002-2014) included new emergency department (ED) or in-hospital diagnosis of non-traumatic AAD confirmed by computed tomography (CT). The controls (2010-2011) were a random age/sex matched sample of patients triaged with undifferentiated acute truncal pain (< 14 days). Finally, we used the beta coefficients derived from multivariate logistic regression of our case control study to assign a numerical strength of association to predictor variables. To mitigate the bias inherent in case control studies we adjusted the beta coefficient for each variable by the diagnostic odds ratio calculated from each systematic review. Pilot validation was performed on a retrospective sample of all those undergoing CTA to rule out AAD at two tertiary care ED over 12 months. Two abstractors were blinded to the final diagnosis. Results: We derived a two-step risk score based on the derivation sample which included 4960 patients(Clinical variables systematic review -9 studies, N=2400, low risk of bias, Kappa 0.9 & Reasons for missed diagnosis systematic review - 11 studies, N=800, low-moderate risk of bias, Kappa 0.89 & Case control study -194 AAD, 776 Controls). Step one is a RAPID assessment for AAD 1) Risk factors 2) Alternative diagnosis in the differential that mimics AAD- ACS, PE, Stroke 3) Physical exam- hypotension, pulse deficit 4) Impression- clinical suspicion of AAD and 5) Discomfort- migrating, tearing, pleuritic, thunderclap, severe pain. If any of the above factors are present proceed to step two. Step two stratifies patients based on history (low, moderate, high suspicion), physical exam (hypotension/pulse deficit) and risk factors. In the pilot validation (N=375,AAD=16) sensitivity was 100% (95%CI 79.4-100) and specificity 36.5% (95%CI 31.5-41.7%). Patients were successfully stratified into low (<2, 0% AAD), moderate (2, 2.2% AAD), high (>2, 19.6% AAD) and critical probability (>3, 62.5% AAD), with up to 36% reduction in imaging. Conclusion: We derived a highly sensitive new clinical risk score with the potential to reduce missed cases of AAD, reduce unnecessary imaging and expedite care.