The immune checkpoint molecule B7-H4 is highly expressed in various types of cancer, but little is known about its role in the development of cervical lesions associated with human papilloma virus (HPV). This study aimed to investigate the role of B7-H4 in cervical lesion progression and the relationship between B7-H4 and HPV infection. This was a retrospective study of tissue samples from 30 patients with cervical cancer, 28 with cervical intraepithelial neoplasia (CIN), and 75 with cervical inflammatory lesions. Serum-soluble B7-H4 (sB7-H4) was assessed by ELISA. Tissue B7-H4 expression was measured by RT-PCR and immunochemistry. Expression of B7-H4 in dendritic cells was assessed by flow cytometry. sB7-H4 increased gradually from the patients with cervical inflammation to patients with cervical cancer and decreased after treatment. sB7-H4 had a diagnostic value in cervical intraepithelial neoplasia (CIN (area under the curve (AUC)=0.8929) and cervical cancer (AUC = 0.9545). B7-H4 expression in inflammatory cervical tissue and peripheral blood dendritic cells (DCs) increased gradually from inflammation to cancer (P < 0.001). sB7-H4 was positively associated with B7-H4 expression in cervical tissue and DCs and with the frequency of CD4(+)CD25(+)Foxp3(+) regulatory T cells (P < 0.001). The level of sB7-H4, and tissue and DC B7-H4 expression were associated with HPV infection (P < 0.001). These data strongly support the use of sB7-H4 for monitoring the progression of cervical cancer associated with HPV, and for evaluating the immune status of the patients.