High-risk papillomavirus type 18 (HPV18) is one of the less represented HPV types in low-grade lesions of the anogenital tract, whereas it occupies the second place in cervical cancer, where it can be found in 16% of the cases worldwide, after HPV16 present in 54% of them. These epidemiological data indicate that HPV18 infection is more prone to carcinogenic progression. The main oncogenic proteins, E6 and E7 of HPV18, are functionally comparable to the homologous proteins of the other high-risk viruses, including HPV16. In this work, we investigated the possibility that the higher oncogenic potential of HPV18 might be due to transcriptional regulation of the E6/E7 oncogenes. By comparing the E6/E7 promoter and enhancer sequences of the mucosal HPV genomes, we identified E2F binding sites specific for HPV18. The E2F family of transcription factors contains activators (E2F1-3) and repressors (E2F4-8) that regulate the transcription of S-phase and mitotic genes and thereby have a crucial role in cell-cycle progression. Surprisingly, we identified E2F5 as a direct activator of HPV18 E6/E7 transcription by sequential silencing of E2F members in HeLa cells. In addition, we could show that E2F5 positively regulates S-phase entry in HeLa cells and that this activation of the cell cycle by a member of the E2F repressor family is specific for HPV18-expressing cells. Diverting the function of E2F5 from a cell-cycle repressor into an activator might contribute to the higher oncogenic potential of HPV18 when compared with other high-risk HPV types.