Abstract Objectives: The tumor suppressor p16INK4a is strongly overexpressed in HPV-associated neoplasia, whereas in normal tissues barely any p16INK4a expression is detectable. Targeting this HPV type-independent antigen by vaccination could represent an interesting complementary therapeutic approach to recently developed HPV-E6/E7-based therapeutic or secondary preventive vaccines. We performed a phase I/IIa peptide vaccination trial to monitor toxicity and immunogenicity of p16INK4a vaccination in patients with advanced HPV-associated cancers. Patients and Methods: 21 patients with p16INK4a-overexpressing, HPV DNA-positive advanced cancers (16 cervical, 5 head and neck) were included. The protocol comprised 12 applications of a synthetic 27mer p16INK4a peptide mixed with Montanide® ISA-51 VG over a six months period. Objectives of the study were clinical safety and changes of humoral and cellular immune responses against the p16INK4a peptide. T cell responses were monitored by interferon-gamma ELISpot and antibodies by ELISA. Conclusions: No vaccine-related toxicity was observed in any of the patients. One patient (head and neck cancer) completed the entire study protocol with stable disease for now 18 months after the last vaccination.11 patients had progressing disease and were excluded from the study after 4 to 12 weeks. 9 patients continue to be vaccinated. While at baseline only one patient had pre-existing T cell responses (CD4) against the p16INK4a peptide, p16INK4a-reactive T cells (CD4) were successfully induced in at least four patients after 4 to 12 vaccine doses. None of the patients had pre-existing p16INK4a antibodies, but 3 patients developed increasing p16INK4a peptide-specific antibody titers after the 5th dose. This is the first study demonstrating that p16INK4a peptide vaccination is safe and well tolerated. The results show that spontaneous immune responses against p16INK4a are rare, but can be induced by p16INK4a peptide vaccination. Further studies are needed to assess clinical efficacy of the approach. Please refer to the protocol of this trial under http://clinicaltrials.gov/show/NCT01462838. Citation Format: Miriam Reuschenbach, Julia Karbach, Franziska Faulstich, Madeleine Sauer, Matthias Kloor, Mohammad-Reza Rafiyan, Claudia Pauligk, Salah AlBatran, Elke Jaeger, Magnus von Knebel Doeberitz. Vicoryx: A phase I/IIa clinical trial using a p16INK4a derived peptide as vaccine in patients with advanced human papillomavirus-associated cancer. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr A12.