Certain types of human papillomavirus (HPV), especially HPV type 16, are associated with proliferative lesions of the cervix uteri that can progress to malignancy. In order to map the linear epitopes of the HPV-encoded proteins, we have synthesized the predicted amino acid sequences of the open reading frames (ORFs) in the early region of HPV 16, as a set of 94 synthetic 20-residue peptides overlapping each other with 5 amino acids. The peptides were tested for reactivity with IgA, IgG and IgM antibodies in the sera of 30 patients with HPV 16-carrying cervical neoplasia. The EI ORF had only low immunoreactivity, but several relatively minor epitopes were identified in the carboxyterminal part. The E2 ORF was found to contain several epitopes that were highly immunoreactive with a majority (up to 87%) of the cervical cancer patients' sera. The E4 ORF had one major, regularly IgA- and IgG-reactive epitope, whereas the E5 and E6 ORFs had only a few minor epitopes. The E7 ORF had several epitopes that were highly immunoreactive, but only with a minority of patients' sera. The 10 most immunoreactive peptides were also analyzed for immunoreactivity with 60 control sera, of which 22 were derived from patients with parotid gland tumors and 38 were derived from healthy volunteers. Most of the peptides were also immunoreactive with the control sera. However, the IgA antibodies, and to some extent the IgG antibodies, were found at much lower levels among the controls.