Abstract Background The clearance of high-risk oncogenic human papillomaviruses (hrHPV) and related cervical lesions is associated with the development of a robust T-cell response. Therapeutic vaccination that induces HPV antigen-specific T cells is a promising approach. Method A 2-vector dosing strategy using Chimpanzee Adenovirus Oxford 1-HPV and Modified Vaccinia virus Ankara-HPV, both encoding the same multiantigen HPV cassette was given on a 0/28-day schedule to participants with persistent cervical hrHPV and a history of low-grade cervical lesions. An open-label lead-in was followed by a randomized, blinded, placebo-controlled main phase. The primary endpoint was the safety of the different dose regimens; secondary endpoints included immunogenicity, and clearance of hrHPV and associated lesions at 12 months. Nine participants were enrolled in the lead-in and 99 were randomized 67:32 to 5 active dose arms or placebo, respectively. Results The regimens were well-tolerated with no grade 3–related treatment emergent adverse events or serious adverse reactions. All dosing regimens generated antigen-specific CD4+ and CD8+ T-cell responses. There was no difference in hrHPV clearance between the pooled active groups and placebo (20/64 [31.3%] versus 10/30 [33.3%]; P > .99), nor in lesion clearance. A trend toward higher hrHPV clearance (60%) was observed with the highest Chimpanzee Adenovirus Oxford 1-HPV doses. No association between the peripheral immune response and clearance was demonstrated. Conclusions A heterologous, multiantigenic HPV 2-component immunotherapy regimen was well-tolerated and immunogenic but did not result in a statistically significant clearance of either hrHPV or the associated cervical lesions in women with persistent high-risk HPV infections. Trial registration EudraCT 2019-001890-98; NCT04607850