Over 33 million people are hospitalized every year in the US, many of whom are seriously ill and experience substantial distress. Clinicians caring for these complex patients also experience distress while simultaneously juggling competing clinical demands. Clinician distress is underrecognized and rarely identified in real-time, however it may impact serious illness care and patient outcomes. The overall purpose of this prospective cohort study was to describe and identify clinician distress trajectories in general medicine hospital clinicians, i.e. physicians and advanced practice providers (APPs) caring for hospitalized seriously ill patients—defined as patients with a high-risk of short-term mortality—and examine how these trajectories affect palliative care delivery.Manuscript 1 employed dimensional analysis to understand the nature of clinician distress. Manuscripts 2 and 3 used data prospectively collected in 2023 with a total of 184 hospital encounters (clinicians, n=68, matched with seriously ill patients, n=151). In Manuscript 2, longitudinal cluster analysis resulted in four distress typologies: low (n=33), moderate (n=47), high (n=34), and variable (n=28). Clinicians also experience symptoms: fatigue (59.3%), stress (57.4%), worry (47.2%), insomnia (33.3%), anger (13.9%), sadness (9.3%), and pain (4.6%). Univariate logistic regression modeling, APPs were significantly more likely (OR=6.159, p=0.00255) than physicians to be in a higher distress typology. Clinicians with fatigue (OR=3.54, p=0.049), insomnia (OR=5.08, p=0.015), worry (OR=4.65, p=0.009), stress (OR=4.20, p=0.031), sadness (OR=21.0, p=0.018) were more likely in a higher distress typology. Manuscript 3 used qualitative interviews with clinicians (n=25) from each typology to comprehensively understand the experience of distress and integrate data. Qualitative themes of distress experience and sources of distress were compared within and between unique typologies. Mixed analysis confirmed typologies with increasing mean distress thermometer scores and clinician higher emotional symptom burden. Findings advance the understanding of in-the-moment psychological distress for hospital clinicians caring for those with serious illness. Not all clinicians experience distress in the same way; however, findings may help personalize interventions for distress based on the four distinct typologies. Immediate implications for healthcare systems in the current post-pandemic era are to acknowledge and quantify clinician distress, and to develop innovative ways to provide support to distressed clinicians.