Objective: To detect the serum level of chemokine CXC motif chemokine 10 (CXCL-10) and Krebs von den lungen-6 (KL-6) in patients with rheumatoid arthritis associated interstitial lung disease (RA-ILD), and to analyze their correlation with RA-ILD, as well as the significance in RA-ILD. Methods: A total of 169 RA patients were enrolled in the study. According to imaging findings of with and without ILD in high-resolution computed tomography scans of chest, the subjects were divided into RA-ILD group and RA-non-ILD group. According to the inclusion and exclusion criteria, 80 patients in each of the two groups were finally selected. Two groups were matched according to the 1 ∶ 1 ratio using propensity score matching (PSM). The serum CXCL-10 and KL-6 levels were detected by enzyme-linked immunosorbent assay. The clinical features, laboratory data and medications between the two groups were compared after PSM and the correlation between serum levels and clinical parameters were analyzed. Binary Logistic regression was used to analyze the risk factors of ILD in the RA patients, and the predictive value of CXCL-10 and KL-6 in RA-ILD was evaluated. Results: In this study, 49 patients with RA-ILD and 49 patients with RA-non-ILD were selected by PSM. The levels of CXCL-10 and KL-6 in the RA-ILD group [64.36 (34.01, 110.18) ng/L, 360.70 (236.35, 715.05) U/mL] were significantly higher than those in the RA-non-ILD group [29.80 (16.89, 40.55) ng/L, 210.69 (159.98, 255.50) U/mL] (all P < 0.001). The results of correlation analysis showed that the level of serum CXCL-10 was positively correlated with the Warrick score on chest CT (r=0.378, P=0.007) and negatively correlated with the percentage of forced vital capacity to the predicted value (FVC%, r=-0.338, P=0.018). And the level of KL-6 was positively correlated with rheumatoid factor (RF, r=0.296, P=0.039) and negatively correlated with FVC% (r=-0.436, P=0.002) and the percentage of diffusion capacity for carbon monoxide to the predicted value (DLCO%, r=-0.426, P=0.002). Both univariate and multivariate Logistic regression analysis showed that CXCL-10 and KL-6 were positively correlated with ILD, the values of OR were 1.035 and 1.023 in CXCL-10 and those were 1.004 and 1.005 in KL-6 respectively (P < 0.05). The ROC curves were plotted with CXCL-10 and KL-6. The area under the curve (AUC) was 0.770 and 0.752 respectively. The AUC of combined detection increased to 0.800. Conclusion: Serum levels of CXCL-10 and KL-6 are significantly elevated in patients with RA-ILD and correlated with the severity of ILD. The combined estimate of them helps to improve the effectiveness of diagnosis.