Background: Frailty is a widely accepted predictor of health outcomes in patients including the critically ill. Biological age is also increasingly recognized as a determinant of chronic health outcomes. Whether these factors are independently predictive of mortality among the critically ill is unknown. We assessed whether biological age, measured as PhenoAge at Intensive Care Unit (ICU) admission, predicts mortality in critically ill patients independent of the Clinical Frailty Scale (CFS). Methods: This single-center retrospective cohort study included adult patients with available CFS and PhenoAge data at admission to ICU, excluding patients with incomplete records for key variables. The Levine PhenoAge model was used to estimate each patient’s biological age (PhenoAge). PhenoAge was then calibrated to generate a regression residual to reflect excessive biological age unexplained by chronological age. Results: Of the 1,073 critically ill adult patients analyzed, 117 died (10.9%) before hospital discharge. PhenoAge and CFS were significantly correlated (correlation coefficient, 0.235; P=0.001). PhenoAge (receiver operating characteristic curve [AUROC], 0.622) and its residuals (AUROC, 0.627) and CFS (AUROC, 0.601) were predictive of hospital mortality, with no significant differences in their ability to differentiate between survivors and non-survivors (paired comparison to CFS: P=0.586 and P=0.537, respectively). PhenoAge interacted with frailty in its effect on mortality (P=0.004) which was particularly prominent among those who were not clinically frail (CFS ≤3). Conclusions PhenoAge and CFS, both measured at ICU admission, independently predicted hospital mortality. PhenoAge showed a notable interaction with frailty, particularly in non-frail patients.