Objective: To investigate the predictive value of serum D-Dimer, interleukin-6 (IL-6) and interleukin-18 (IL-18) on refractory mycoplasma pneumoniae pneumonia (RMPP) in children. Methods: A total of 150 children with mycoplasma pneumoniae pneumonia (MPP) admitted to our hospital from May 2020 to May 2021 were selected as the research subjects and divided into a RMPP group (n=52) and a general mycoplasma pneumoniae pneumonia (GMPP) group (n=98) according to the clinical diagnostic criteria. The general basic data, chest CT imaging data and serum indexes before treatment [D-Dimer, C-reactive protein (CRP), procalcitonin (PCT), tumor necrosis factor-α (TNF-α), IL-6, and IL-18] were compared between the 2 groups. Logistic regression was used to analyze the independent influencing factors of RMPP, and receiver operating characteristic curve (ROC) was drawn to evaluate the clinical value of D-Dimer, IL-6 and IL-18 in the diagnosis of RMPP. Results: The proportion of pleural effusion, pulmonary consolidation, atelectasis and serum levels of D-Dimer, CRP, PCT, IL-6 and IL-18 in RMPP group were significantly higher than those in the GMPP group (P<0.05). Logistic regression analysis showed Pulmonary consolidation, pleural effusion, atelectasis and increased expression of serum D-Dimer, CRP, PCT, IL-6 and IL-18 were independent risk factors for RMPP (P<0.05). ROC curve showed that the areas under the curve of serum D-Dimer, IL-6 and IL-18 for predicting RMPP were 0.830, 0.825 and 0.860, respectively, and the cut-off values were 0.56 mg/L, 24.96 pg/mL and 393.51 pg/mL, respectively. Conclusion: Serum D-Dimer, IL-6 and IL-18 can be used as early predictors of RMPP in children.