Abstract
Background/Objectives: Cardiac arrest (CA) continues to be one of the leading causes of mortality and long-term neurological disability worldwide. Accurate early neuroprognostication after return of spontaneous circulation is essential for guiding post-resuscitation care. The calcium-binding astrocytic protein S100B has been identified as a potential biomarker for hypoxic–ischemic brain injury. This systematic review and meta-analysis assessed the prognostic and diagnostic efficacy of serum S100B in forecasting neurological outcomes after CA. Methods: Thorough searches of PubMed, Embase, Scopus, Web of Science, CENTRAL, and CINAHL from their inception to November 2025 uncovered 40 observational studies. Results: Pooled analyses employing random-effects models revealed markedly reduced S100B concentrations in patients with favourable neurological outcomes compared to those with unfavourable outcomes (standardized mean difference −1.78, 95%CI: −2.25 to −1.31; p < 0.001). The diagnostic accuracy was high, with pooled sensitivity and specificity of 0.63 and 0.93, respectively, and an area under the curve of 0.89 (95% CI 0.85–0.92). Subgroup and sensitivity analyses confirmed the robustness of these findings across various study populations and temporal points, with negligible evidence of publication bias. Conclusions: These results indicate that serum S100B is a reliable early biomarker of neurological prognosis after CA. Incorporating S100B into multimodal predictive frameworks may enhance post-resuscitation decision-making.