Background: Generalized weakness and fatigue are underexplored symptoms in emergency medicine. Triage tools often underestimate patients presenting to the emergency department (ED) with these nonspecific symptoms (Nemec et al., 2010). At the same time, physicians' disease severity rating (DSR) on a scale from 0 (not sick at all) to 10 (extremely sick) predicts key outcomes in ED patients (Beglinger et al., 2015; Rohacek et al., 2015). Our goals were (1) to characterize ED patients with weakness and/or fatigue (W|F); to explore (2) to what extent physicians' DSR at triage can predict five key outcomes in ED patients with W|F; (3) how well DSR performs relative to two commonly used benchmark methods, the Emergency Severity Index (ESI) and the Charlson Comorbidity Index (CCI); (4) to what extent DSR provides predictive information beyond ESI, CCI, or their linear combination, i.e., whether ESI and CCI should be used alone or in combination with DSR; and (5) to what extent ESI, CCI, or their linear combination provide predictive information beyond DSR alone, i.e., whether DSR should be used alone or in combination with ESI and / or CCI., Methods: Prospective observational study between 2013-2015 (analysis in 2018-2020, study team blinded to hypothesis) conducted at a single center. We study an all-comer cohort of 3,960 patients (48% female patients, median age = 51 years, 94% completed 1-year follow-up). We looked at two primary outcomes (acute morbidity (Bingisser et al., 2017; Weigel et al., 2017) and all-cause 1- year mortality) and three secondary outcomes (in-hospital mortality, hospitalization and transfer to ICU). We assessed the predictive power (i.e., resolution, measured as the Area under the ROC Curve, AUC) of the scores and, using logistic regression, their linear combinations., Findings: Compared to patients without W|F (n = 3,227), patients with W|F (n = 733) showed higher prevalences for all five outcomes, reported more symptoms across both genders, and received higher DSRs (median = 4; interquartile range (IQR) = 3-6 vs. median = 3; IQR = 2-5). DSR predicted all five outcomes well above chance (i.e., AUCs > ~0.70), similarly well for both patients with and without W|F, and as good as or better than ESI and CCI in patients with and without W|F (except for 1-year mortality where CCI performs better). For acute morbidity, hospitalization, and transfer to ICU there is clear evidence that adding DSR to ESI and/or CCI improves predictions for both patient groups; for 1-year mortality and in-hospital mortality this holds for most, but not all comparisons. Adding ESI and/or CCI to DSR generally did not improve performance or even decreased it., Conclusions: The use of physicians' disease severity rating has never been investigated in patients with generalized weakness and fatigue. We show that physicians' prediction of acute morbidity, mortality, hospitalization, and transfer to ICU through their DSR is also accurate in these patients. Across all patients, DSR is less predictive of acute morbidity for female than male patients, however. Future research should investigate how emergency physicians judge their patients' clinical state at triage and how this can be improved and used in simple decision aids., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: The research group at the University of Basel hosts www.medstandards.ch, a decision-support tool that is based on symptoms at emergency presentation. Conflicts of interest Mirjam Annina Jenny Talks or teaching for which I received modest honoraria by the following organizations: • German National Association of Statutory Health Insurance Physicians • Dr. Risch Laboratories (Buchs, Switzerland) • Health Ministry Baden-Württemberg (Germany) • mediX AG(Zurich, Switzerland) • VDE e.V. (Germany) • Geburtshülfliche Gesellschaft zu Hamburg (Obstetrics Association Hamburg) • Landesgesundheitsprojekte e.V. (Germany) • Gesundheitsforen Leipzig GmbH (Germany) • Deutsche Menopause Gesellschaft e.V. (German Menopause Association) • Deutscher Berufsverband für Pflegeberufe (DBfK) Nordwest e.V. (German Nursing Association) • Swiss Rheumatism Symposium • Sana Herzchirurgie Stuttgart GmbH (Germany) The Harding Center (Mirjam Jenny's employer) has received funding from: • AOK Insurance (Germany) • Helsana Insurance (Switzerland) • BKK Viactiv Insurance (Switzerland) • German Football Association • Microsoft Research New Work • David Harding (Winton Philanthropies) • German Federal Institute for Risk Assessment • ERGO Insurances (Germany) • Goethe University of Frankfurt (Germany) • German Ministry for Transport and digital Infrastructure • German Ministry for Justice and Consumer Protection • German Aerospace Center This does not alter our adherence to PLOS ONE policies on sharing data and materials.