BACKGROUND Targeted temperature management (TTM) is a common therapeutic intervention, yet its cost-effectiveness remains uncertain. This study aimed to evaluate the real-world cost-effectiveness of TTM compared with that of conventional care in adult out-of-hospital cardiac arrest (OHCA) survivors using clinical patient-level data. METHODS: We conducted a retrospective cohort study at an academic medical center in the USA to assess the cost-effectiveness of TTM in adult non-traumatic OHCA survivors between 1 January, 2019 and 30 June, 2023. The primary outcome was survival to hospital discharge. Incremental cost-effectiveness ratios (ICERs) were calculated and compared with various decision makers’ willingness to pay. Cost-effectiveness acceptability curves were utilized to evaluate the economic attractiveness of TTM. Uncertainty about the incremental cost and effect was explored with a 95% confidence ellipse. RESULTS: Among 925 non-traumatic OHCA survivors, only 30 (3%) received TTM. After adjusting for potential confounders, the TTM group did not demonstrate a significantly lower cost (delta cost -$5,141, 95% confidence interval [95% CI]: $-35,347 to $25,065, P=0.79) and higher survival to hospital discharge (delta effect 6%, 95% CI: -11% to 23%, P=0.41). Additionally, a 95% confidence ellipse indicated uncertainty reflected by evidence that the true value of the ICER could be in any of the quadrants of the cost-effectiveness plane. CONCLUSION: Although TTM did not demonstrate a clear survival benefit in this study, its potential cost-effectiveness warrants further investigation with larger sample sizes. These findings highlight the need for additional research to optimize TTM use in OHCA care and inform resource allocation decisions.