Background: Cystatin C (CysC) predicts adverse outcomes in heart failure (HF), yet its prognostic value relative to underlying renal function remains undefined. We aimed to determine the association between serum CysC and 1-year readmission risk in HF patients stratified by chronic kidney disease (CKD) status. Methods: This retrospective cohort study analyzed 2,008 hospitalized HF patients. Based on CKD status, patients were categorized into non-CKD and CKD groups. Serum CysC levels were analyzed as both continuous variable and in tertiles. The association with 1-year readmission was assessed using multivariable Cox proportional hazards models. Results: Overall, each 1 mg/L increase in CysC was independently associated with an 11% higher risk of re-admission (adjusted HR: 1.11, 95% CI: 1.01-1.23, p=0.003). A significant interaction with CKD status was found (p=0.003). In the non-CKD group, elevated CysC (>1.98 mg/L) was associated with a 51% increased risk (adjusted HR: 1.51, 95% CI: 1.18-1.92, p=0.001), with a non-linear threshold effect identified at 0.998 mg/L. Conversely, no significant association was observed in CKD patients (adjusted HR: 0.96, 95% CI: 0.82-1.12, p=0.576). Conclusions: Elevated serum CysC is a potent predictor of 1-year readmission in HF patients without CKD, but not in those with established CKD. Its prognostic utility is therefore highly dependent on renal context, highlighting its greatest value in patients without advanced renal dysfunction.