Abstract Background Assessing health-related quality of life (HRQoL) in patients with acute coronary syndromes (ACS) could provide insight into predicting major adverse cardiovascular events (MACE) and all-cause death. Purpose To investigate the association of baseline HRQoL and its change within the first year post-ACS with the incidence of MACE and all-cause death. Methods Participants in the SPUM-ACS study, a multicenter cohort of patients hospitalized for ACS at four Swiss university hospitals from 2007 and 2021 and followed-up for a median duration of 6.6 years, were evaluated for HRQoL at baseline and one-year post-discharge using the EQ-5D-3L index and visual analogue scale (VAS). The EQ-5D-3L index is derived from five health dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Baseline HRQoL and its change within the first year post-ACS, alongside the individual health dimensions, were analyzed in relation to the risk of subsequent MACE (composite of myocardial infarction, stroke or transient ischemic attack, coronary revascularization, and cardiovascular death) and all-cause death using Cox proportional hazards models, adjusting for sociodemographic, lifestyle factors, and medical history. Results 2499 patients with ACS (mean age 62±12 years, 80% males), primarily undergoing percutaneous coronary revascularization, were included. Over a median follow-up of 6.6 years, 25% experienced MACE and 13% died from any cause. Overall, HRQoL improved in the first year post-ACS, with the EQ-5D-3L index increasing from 0.74 to 0.81 and the VAS from 68 to 76 (p<0.001). At baseline, 80% reported some problem in at least one health dimension, mainly anxiety/depression (36%), pain/discomfort (35%), and mobility (27%). By the first year, 58% had no problem or improved in one or more dimensions; however, 38% declined in at least one dimension, particularly in pain/discomfort (26%), or anxiety/depression (16%). The baseline VAS, but not EQ-5D-3L index, was inversely associated with the hazard of subsequent MACE and all-cause death (HR=1.06 [1.01, 1.11] per 0.1-unit and 1.10 [1.03, 1.19] per 10-unit decrease, respectively). Problems with pain/discomfort were associated with MACE (HR=1.20 [1.00, 1.44]); and mobility, self-care and usual activities with all-cause death (HR=1.36 [1.04, 1.79], 1.44 [1.04, 1.98] and 1.37 [1.04, 1.80], respectively) (Figure 1). First-year EQ-5D-3L index and VAS change were inversely associated with the hazard of MACE (HR=1.11 [1.04, 1.18] per 0.1-unit and 1.16 [1.07, 1.25] per 10-unit decrease) and all-cause death (HR=1.13 [1.04, 1.23] per 0.1 and 1.17 [1.06, 1.30] per 10-unit decrease, respectively) (Figure 2). Conclusion HRQoL at baseline and its change within the first year after ACS are associated with the risk of adverse events, suggesting HRQoL might be a valuable predictive indicator for long-term outcomes in patients with ACS.Figure 1Figure 2