Background <p>It has been reported that interleukin-10 (IL-10) is associated with some immune-mediated diseases; however, its relationship with histiocytic necrotizing lymphadenitis (HNL) has not been reported. This study aimed to preliminarily investigate the relationship between IL-10 and HNL.</p> Methods <p>This study included 35 children with HNL and 35 healthy controls. Plasma IL-10 levels were detected by ELISA. The gene polymorphisms at -1082A/G, -819T/C, and -592 A/C in the IL-10 promoter were analyzed by Sanger sequencing. Differences in IL-10 expression, allele and genotype frequencies between the two groups were statistically compared.</p> Results <p>IL-10 levels were significantly higher in children with HNL than in the control group (<i>P</i> = 0.001). However, no significant differences were observed between the two groups in allele frequencies, genotype distributions of the three IL-10 promoter polymorphisms, or the haplotypes constituted by these loci.</p> Conclusions <p>These findings suggest that IL-10 may contribute to HNL pathogenesis, while no significant association between the IL-10 promoter polymorphisms (-1082A/G, -819T/C, -592A/C) and pediatric HNL susceptibility was found in this exploratory analysis. A potential genetic association cannot be excluded and further studies with a larger sample size are warranted.</p>