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Background and Aims: Activin A is a key regulator in liver regeneration, but data evaluating its role in humans after hepatic surgery are limited. In this study we explore the predictive role of circulating activin A, its antagonist follistatin-like 3 (FSTL-3), and their ratio for posthepatectomy liver failure (PHLF) and monitor their levels after surgery, to evaluate their role in human liver regeneration., Methods: Activin A and FSTL-3 levels were assessed in 59 patients undergoing liver surgery. Using receiver operating characteristic analysis, we evaluated the predictive potential of activin A, FSTL-3, and their ratio., Results: While perioperative dynamics of activin A and FSTL3 were significantly affected by hepatic resection (activin A P  = .045, FSTL-3 P  = .005), their functionally relevant ratio did not significantly change ( P  = .528). Neither activin A nor FSTL-3 alone but only their ratio exhibited a significant predictive potential for PHLF (area under the curve: 0.789, P  = .038). Patients with low preoperative activin A/FSTL-3 ratio were found to more frequently suffer from PHLF (0.017) and morbidity (0.005)., Conclusion: Activin A/FSTL-3 ratio predicts PHLF and morbidity. Its significance in preoperative patient assessment needs to be further validated in larger, independent cohorts., (© 2023 The Authors.)