Papillomaviruses infect epithelia of the skin and mucous membranes and cause benign or malignant tumours in animals and in humans. The viruses are highly species-specific, and cell culture systems for propagating human papillomaviruses (HPVs) do not exist. However, there are several animal papillomavirus models. In the cottontail rabbit papillomavirus (CRPV) system, we demonstrated that recombinant CRPV virus-like particles (VLPs) consisting of the capsid proteins L1 or L1+L2 can be produced in the yeast Saccharomyces cerevisiae. Three immunizations with L1 VLPs formulated on aluminum adjuvant at 1-100 micrograms dose-1 efficiently protected rabbits from challenge with CRPV. Sera of immunized rabbits were shown to contain high-titered serum antibodies to CRPV L1 VLPs and to neutralize CRPV in vitro. Our results suggest that recombinant yeast-derived VLPs could be the basis for a candidate HPV vaccine.