Abstract: Objective To investigate the value of C-X-C motif chemokine ligand 16 (CXCL16) combined with C-C motif chemokine ligand 21 (CCL21) in predicting pulmonary function impairment and disease control in children with childhood allergic rhinitis-asthma syndrome (CARAS). Methods A total of 108 children with CARAS (CARAS group), 108 children with simple asthma (asthma group), and 108 children with simple allergic rhinitis (AR group) admitted to Baoji People′s Hospital of Shaanxi Province from January 2022 to December 2024 were prospectively selected. The levels of CXCL16 and CCL21 in peripheral blood and pulmonary function indicatorspeak expiratory flow (PEF), percentage of predicted forced expiratory volume in one second (FEV₁%pred), and ratio of forced expiratory volume in one second to forced vital capacity (FEV₁/FVC)were compared among the groups. Pearson correlation analysis was used to explore the correlations of the levels of CXCL16 and CCL21 in peripheral blood with pulmonary function indicators in children with CARAS. After completion of treatment, a 3-month follow-up was conducted, and the children with CARAS were divided into poorly controlled group and well-controlled group according to disease control status. Multivariate Logistic regression and receiver operating characteristic (ROC) curve analyses were used to analyze the relationships of the levels of CXCL16 and CCL21 in peripheral blood with poor disease control in children with CARAS and their predictive efficacy. Results The levels of CXCL16 and CCL21 in peripheral blood in the AR group, asthma group, and CARAS group increased sequentially, while PEF, FEV₁%pred, and FEV₁/FVC decreased sequentially (P < 0.05). There were no statistically significant differences in the levels of CXCL16 and CCL21 in peripheral blood, PEF, FEV1%pred, and FEV₁/FVC among the pollen group, dust mite group, animal dander group, and other groups (P>0.05). Pearson correlation analysis showed that the levels of CXCL16 and CCL21 in peripheral blood in children with CARAS were negatively correlated with PEF, FEV1%pred, and FEV₁/FVC (r=-0.629, -0.668, -0.710, -0.645, -0.672, -0.697, P < 0.001). After a 3-month follow-up, the rate of poor disease control after treatment among the 108 children with CARAS was 47.22% (51/108). Univariate analysis showed that total immunoglobulin E (IgE), eosinophil (EOS) count, fractional exhaled nitric oxide (FeNO), PEF, FEV₁%pred, FEV₁/FVC, CXCL16, and CCL21 were associated with poor disease control in children with CARAS (P < 0.05). Logistic regression analysis showed that high EOS count, high FeNO, high CXCL16, and high CCL21 were independent risk factors for poor disease control in children with CARAS (P < 0.05). ROC curve analysis showed that the areas under the curve for peripheral blood CXCL16 level, CCL21 level, and their combination in predicting poor disease control in children with CARAS were 0.843, 0.820, and 0.917, respectively. The predictive efficacy of their combination was better than that of peripheral blood CXCL16 level or CCL21 level alone (Z=2.054, 2.312; P=0.040, 0.021). Conclusion Elevated levels of CXCL16 and CCL21 in peripheral blood are closely associated with decreased pulmonary function and poor disease control in children with CARAS, and their combination has a high predictive efficacy for poor disease control.