Objective To investigate the relationship between the vaginal microecology and CC chemokine ligand 28(CCL28)expression levels in the vaginal lavage fluid of patients with persistent high-risk human papillomavirus(HR-HPV)infection.Methods A total of 132 patients with HR-HPV infection at Tangshan Maternal and Child Health Hospital from April 2021 to April 2023 were selected as study subjects.Patients with HR-HPV infection were categorized into the single infection group and the persistent infection group according to the review results.The CCL28 and vaginal microecological indicators of the two groups were compared.Logistic regression was used to analyze the risk factors for persistent HR-HPV infection.The dose-response relationship between CCL28 and persistent HR-HPV infection was analyzed by fitting restricted cubic splines with logistic regression.Spearman and multiple linear regression were used to analyze the relationship between CCL28 and vaginal microecological indicators.Results After the re-examination of patients,there were 84(63.64％)cases of single infection and 48(36.36％)cases of persistent infection.The percentage of colony density grade Ⅰ(54.17％vs 16.67％),colony diversity grade Ⅰ(47.92％),pH＞4.5(47.92％),hydrogen peroxide positivity(54.17％),and vaginal microecological imbalance(66.67％),and the level of CCL28[83.63(77.11,99.62)ng/L]in the persistent infection group were higher than those of the single infection group[16.76％,21.43％,15.48％,30.95％,41.67％,71.11(58.12,82.16)ng/L],and the differences were statistically significant(x2/Z=5.064～20.338,all P＜0.05).Logistic regression analysis showed that colony density grade Ⅰ(OR=3.556,95％CI:1.241～10.194,P=0.018),PH＞4.5(OR=4.366,95％CI:1.164～16.380,P=0.029),and high CCL28 levels(OR=1.048,95％CI:1.018～1.080,P=0.002)were independent risk factors for persistent infection in HR-HPV-infected patients.Logistic regression fitting restricted cubic splines showed a linear relationship between CCL28 and persistent HR-HPV infection(nonlinear test x2=0.61,P=0.437).Spearman correlation analysis results showed that CCL28 was positively correlated with age(r=0.205,P=0.018),colony density(r=0.429,P＜0.001),colony diversity(r=0.389,P＜0.001),pH(r=0.357,P＜0.00l),hydrogen peroxide(r=0.409,P＜0.001),leukocyte esterase(r=0.392,P＜0.00l),and vaginal microecology(r=0.473,P＜0.001).Linear regression analysis showed that colony density(β=12.295,P=0.003)and colony diversity(β=9.196,P=0.032)were independently associated with CCL28.Conclusion Colony density and colony diversity were independently correlated with CCL28.Colony density grade Ⅰ,pH＞4.5,and high CCL28 levels suggest an increased risk of persistent infection in patients with HR-HPV infection.