BACKGROUND AND AIMS: Stress hyperglycemia ratio (SHR) and pan-immune-inflammation value (PIV) are novel prognostic markers associated with metabolic changes and chronic inflammation, but their association with mortality risk in individuals with overweight and obesity remains unknown. We aimed to investigate impact of SHR and PIV on mortality risk in individuals with overweight and obesity. METHODS AND RESULTS: This cohort study included 16,703 U S adults with overweight and obesity. SHR and PIV were estimated, and Cox regression, ROC, and Kaplan-Meier curves analyzed their associations with all-cause and cause-specific mortality. Subgroup and interaction analyses tested SHR and PIV consistency. Over a median follow-up of 110 months, there were 2432 all-cause deaths (14.6 %), including 677 cardiovascular, 577 cancer, and 130 cerebrovascular deaths. Participants were categorized by optimal SHR (≥1.038 or <
1.038) and PIV (≥301 or <
301) cutoffs. High SHR was associated with higher overall and cause-specific mortality (log-rank p <
0.001). High PIV was linked to increased risks of overall, cardiovascular, and cancer mortality (log-rank p <
0.001). Multivariate Cox models showed elevated SHR was associated with increased all-cause, cardiovascular, and cancer mortality (HR:1.59
95%CI: 1.34-1.89
HR:1.45
95%CI: 1.03-2.04
HR:1.66
95%CI: 1.15-2.38, respectively). Elevated PIV was linked to higher all-cause and cardiovascular mortality (HR: 1.18
95%CI: 1.02-1.37
HR:1.35
95%CI: 1.02-1.79, respectively). Poorer survival was noted in obesity + high SHR and overweight + high PIV subgroups (log-rank p <
0.001). CONCLUSIONS: Elevated SHR and PIV are significant predictors of increased all-cause and cause-specific mortality in individuals with overweight and obesity.