Abstract Body (Do not enter title and authors here): Introduction: There is little data on how symptoms change after patients discharge from heart failure (HF) hospitalizations (HFH). The ability of clinicians to address symptoms is hindered by few associations between biomarkers of HF pathology and patients’ symptoms. Aim: To characterize physical and psychological HF symptoms from HFH to 6 months post-discharge and to examine associations of peripheral blood biomarkers with HF symptoms over time. Method: This study used an observational longitudinal design from HFH through 6 months post-discharge in 49 patients with NYHA Class III HF. Physical [HF Somatic Perception Scale (HFSPS), Multi-Dimensional Fatigue Inventory (MDFI) physical scale, Pittsburg Sleep Quality Index (PSQI), and PROMIS Pain Interference] and psychological [Patient Health Questionnaire 8 (PHQ8), MDFI mental scale, and PROMIS Anxiety] symptom measures were collected during HFH, and at 1-, 3-, and 6-months post-discharge. Latent growth curve modeling was used to characterize trajectories in physical and psychological symptoms. Symptom intercepts (values at HFH) and slopes (change over time) were regressed on biomarkers (IL6, sST2, hsCRP, BNP, Galectin-3) collected at HFH. Results: Participants (n=49) were, on average 68±10 years, 53% women, with an average ejection fraction of 44±20%. Physical fatigue and physical HF symptoms (HFSPS) decreased significantly from HFH through 6-months post hospitalization (HFSPS: p<0.001; Physical fatigue: p<0.007). Psychological symptoms [MDFI mental scale, depressive symptoms (PHQ8), and anxiety (PROMIS Anxiety)] did not change significantly from HFH through 6 months post-discharge. During HFH, higher levels of Galectin-3 were associated with more severe physical fatigue (β=2.30, p=0.019) and worse sleep quality (β=3.21, p=0.005). Higher levels of IL6 were associated with better sleep quality (β= -2.22, p=0.005) and higher levels of sST2 were associated with more severe mental fatigue (β=1.63, p=0.003). For symptoms with significant changes over time (MDFI Physical, HFSPS), no biomarkers were associated with those changes in symptoms post-discharge. Conclusion: Physical symptoms improved to 6 months after HFH while psychological symptoms did not improve after discharge suggesting psychological symptoms need more attention after HFH. Novel associations between biomarkers and HF symptoms were identified that provide new insights into the biological mechanisms of physical and psychological HF symptoms.