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ObjectiveThis study aimed to compare the sensitivity and specificity of diagnosis between the third heart sound (S3) and left ventricular ejection fraction (LVEF) in heart failure (HF).MethodsRelevant studies were searched in PubMed, SinoMed, China National Knowledge Infrastructure, and the Cochrane Trial Register until February 20, 2022. The sensitivity, specificity, likelihood ratio (LR), and diagnostic odds ratio (DOR) were pooled. The symmetric receiver operator characteristic curve (SROC) and Fagan’s nomogram were drawn. The source of heterogeneity was explored by meta-regression and subgroup analysis.ResultsA total of 19 studies, involving 5,614 participants, were included. The combined sensitivity of S3 was 0.23 [95% confidence interval (CI) (0.15–0.33), specificity was 0.94 [95% CI (0.82–0.98)], area under the SROC curve was 0.49, and the DOR was 4.55; while the sensitivity of LVEF was 0.70 [95% CI (0.53–0.83)], specificity was 0.79 [95% CI (0.75–0.82)], area under the SROC curve was 0.79, and the DOR was 8.64. No publication bias was detected in Deeks’ funnel plot. The prospective design, partial verification bias, and blind contributed to the heterogeneity in specificity, while adequate description of study participants contributed to the heterogeneity in sensitivity. In Fagan’s nomogram, the post-test probability was 48% when the pre-test probability was set as 20%, while in LVEF, the post-test probability was 45% when the pre-test probability was set as 20%.ConclusionThe use of S3 alone presented lower sensitivity in diagnosing HF compared with LVEF, whereas it was useful in early pathological assessment.