Abstract: Objective To investigate the roles of atypical lymphocytes, interleukin-6 (IL-6), and erythrocyte sedimentation rate (ESR) in the etiological diagnosis and disease severity stratification of pediatric respiratory tract infections. Methods A total of 216 children with respiratory tract infections and normal blood routine results from May 2022 to June 2024 were selected as study subjects. Based on etiological findings, they were divided into bacterial group (n=55), viral group (n=85), and mycoplasma group (n=76). Additionally, 50 healthy children during the same period were selected as control group. The levels of atypical lymphocytes, IL-6, and ESR were compared among different groups and between children with varying disease severities. The diagnostic value of atypical lymphocytes, IL-6, and ESR alone and their combination for pathogen identification was analyzed using thereceiver operating characteristic (ROC) curve. The correlations of atypical lymphocytes, IL-6, ESR, with disease severity were analyzed using the Spearman method. Results Compared with the control group, the viral group had the highest proportion of atypical lymphocytes, followed by the mycoplasma group, and the bacterial group had the lowest. The viral group had the lowest IL-6 level, followed by the mycoplasma group, and the bacterial group had the highest. The bacterial group had the highest ESR, followed by the viral group, and the mycoplasma group had the lowest. Pairwise comparisons of these indicators among different groups all showed statistically significant differences (P < 0.05). ROC curve analysis revealed that atypical lymphocytes had the largest area under the curve (AUC) for distinguishing viruses, while IL-6 and ESR had the largest AUC for distinguishing bacteria. The AUC values for the combined use of atypical lymphocytes, IL-6, and ESR in differentiating bacteria, viruses, and mycoplasma were 0.911, 0.916, and 0.922, respectively, which were greater than the AUC values for each indicator alone in diagnosing these pathogens, with statistically significant differences (P < 0.05). Children with severe pneumonia had higher levels of atypical lymphocytes, IL-6, and ESR compared to those with ordinary pneumonia and upper respiratory tract infections. Children with ordinary pneumonia had higher levels of these indicators compared to those with upper respiratory tract infections, with all differences being statistically significant (P < 0.05). Spearman correlation analysis demonstrated a significant positive correlation between atypical lymphocytes, IL-6, ESR, and stratification of disease severity (upper respiratory tract infection=1, ordinary pneumonia=2, severe pneumonia=3) (P < 0.05). Conclusion Atypical lymphocytes, IL-6, and ESR are associated with the pathogen type and disease severity in children with respiratory tract infections and normal blood routine results. Combined detection of these indicators has a high discriminatory value for different pathogens.