Background <p>The association between stress hyperglycemia ratio (SHR), quantifying acute hyperglycemia relative to chronic glycemic status, and outcomes in patients on invasive mechanical ventilation (IMV) remains inadequately explored. This study aimed to evaluate the prognostic value of SHR concerning mortality and its potential to inform treatment decisions for patients undergoing IMV.</p> Methods <p>MIMIC-IV database provided analysis data. The endpoints were one-year or intensive care unit all-cause mortality. Survival analysis, Cox regression, restricted cubic splines and subgroup analyses were performed. Propensity score overlap-weighting as sensitivity analysis ensured robustness.</p> Results <p>It encompassed 3600 patients, identifying an optimal cutoff for the SHR of 1.37 for mortality risk stratification. Kaplan-Meier curves and Cox models indicated that increased SHR levels were linked to an elevated likelihood of all-cause mortality, with adjusted hazard ratio of 1.43 (95% confidence interval: 1.22–1.67). This pattern continued in most subgroups, except for those with varying levels of red cell distribution width (RDW) or Acute Physiology Scores III (APS III) (<i>p</i> for interaction &lt; 0.05). Subsequent analyses suggested that antibiotic efficacy was amplified in high-SHR patients (<i>p</i> = 0.025), while glucocorticoid-associated risks were attenuated (<i>p</i> = 0.037). Sensitivity analysis confirmed this correlation.</p> Conclusion <p>This study explored the positive association between SHR levels and mortality risk in patients on invasive mechanical ventilation. SHR shows promise as a risk stratification tool and generates hypotheses about differential treatment responses requiring prospective validation.</p> Clinical trial number <p>Not applicable.</p>