Background <p>The serum creatinine-to-cystatin C (Cr/CysC) ratio is associated with the prognosis of various diseases. Renal dysfunction in patients with stroke is associated with an increased risk of mortality and poor functional outcomes. This study aimed to evaluate the predictive role of the serum Cr/CysC ratio for renal dysfunction occurrence in patients with acute ischemic stroke (AIS).</p> Methods <p>We enrolled patients from the China National Stroke Registry-Ⅲ (CNSR-Ⅲ) database, who were classified into four groups (Q1–Q4, from low to high) according to the quartiles of the baseline serum Cr/CysC ratio. The main endpoints were occurrence of incident chronic kidney disease (CKD) and rapid decline in kidney function (RDKF) at 1 year after AIS. Multivariate logistic regression models were applied to analyze the relationship between the Cr/CysC ratio and main endpoints.</p> Results <p>After adjusting for confounding factors and using Q1 as the reference, the Q3 and Q4 quartiles of the baseline serum Cr/CysC ratio were negatively associated with incident CKD risk at 1 year (Q3 vs. Q1: adjusted odds ratio [aOR] 0.41, 95% confidence interval [CI] 0.21–0.80, <i>P</i> = 0.009; Q4 vs. Q1: aOR 0.39, 95%CI 0.18–0.81, <i>P</i> = 0.012). Furthermore, the Q2–Q4 quartiles of the baseline serum Cr/CysC ratio were negatively associated with RDKF risk at 1 year (Q2 vs. Q1: aOR 0.77, 95%CI 0.63–0.94, <i>P</i> = 0.009; Q3 vs. Q1: aOR 0.62, 95%CI 0.50–0.77, <i>P</i> &lt; 0.001; Q4 vs. Q1: aOR 0.44, 95%CI 0.34–0.56, <i>P</i> &lt; 0.001). The concordance statistic was 0.78 for incident CKD and 0.67 for RDKF.</p> Conclusions <p>A lower baseline serum Cr/CysC ratio was associated with a higher risk of incident CKD and RDKF 1 year after AIS. The serum Cr/CysC ratio may serve as an important biomarker for predicting renal function outcomes after AIS.</p> Trial registration <p>This CNSR-Ⅲ study was registered at ClinicalTrials.gov (identifier: NCT04290494).</p>