Cottontail rabbit papillomavirus is the major papillomavirus animal model with which to study host-virus interactions. As with human papillomaviruses, papillomas may spontaneously regress, persist, or progress to carcinoma. Here we show that the majority (88%) of regressor rabbits had antibody to the nonstructural protein E2 compared to 29% in animals with persisting papilloma. The antibody response to other nonstructural viral proteins was the same for rabbits with regressing and persisting papilloma. The cellular immune response was measured by an in vitro proliferation assay. The responses to E6 and E7 were infrequent and similar in papilloma-bearing and in regressor rabbits and no rabbits responded to E1. In contrast, the response to E2 was more frequent in regressor rabbits. These data suggest that E2-specific immune responses may play a role in tumor regression.