We have investigated the expression in vivo and in vitro of HLA-DR in pre-invasive squamous-cell neoplasia of the uterine cervix. Immunohistochemistry of cervical biopsies demonstrated HLA-DR expression by cervical keratinocytes in 50% of cases of high-grade squamous intra-epithelial neoplasia, although the molecule was rarely expressed in low-grade squamous intra-epithelial neoplasia and was absent from normal ectocervical cells. HLA-DR-positive high-grade lesions were associated with significantly greater numbers of T lymphocytes in the immediately sub-epithelial stroma than were the HLA-DR-negative high-grade lesions. In vitro HLA-DR expression was absent from normal ectocervical epithelium, and from the HPV type 16 containing cell lines W12 (representing low-grade squamous intra-epithelial neoplasia) and CaSki and SiHa (each representing high-grade squamous intra-epithelial neoplasia), both in monolayer and in organotypic raft culture. HLA-DR expression was induced in all cell types following recombinant interferon gamma treatment. Our data suggest that the expression of HLA-DR by keratinocytes in some high-grade cervical lesions in vivo may be due to local induction of the molecule by pro-inflammatory cytokines released by immunocompetent cells. The functional significance of HLA-DR positivity in enabling an effective host immune response to neoplastic cervical keratinocytes remains unclear.