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Lesions generated by infection with cottontail rabbit papillomavirus frequently undergo spontaneous regression. The purpose of this immunohistochemical study was to compare leukocyte and papilloma cell proliferation in progressing and regressing papillomas and to test the hypothesis that regression was associated with an inhibition of papilloma cell proliferation. The monoclonal antibodies (MAbs) MAb-019 (specific for DNA/bromodeoxyuridine [BrdU] complexes), Ki-67 (specific for actively proliferating cells), L11/135 (specific for rabbit T cells), and 2C4 (specific for rabbit class II antigen) were used for this purpose. In progressing papillomas, there were few leukocytes (< 1%) in the dermis that stained with MAb-019 and Ki-67, whereas these antibodies stained 4.5% and 6.8% of the intraepidermal leukocytes, respectively. Regressing papillomas contained conspicuous leukocytic infiltrates in the dermis, of which 76.9% were L11/135-positive T cells. However, few intradermal leukocytes (< 3%) stained positively with MAb-019 and Ki-67 MAbs, despite expressing rabbit class II antigen. The epidermis of regressing papillomas contained a higher percentage of MAb-019- and Ki-67-positive leukocytes than the epidermis of progressing papillomas. Intraepidermal leukocytes in progressing and regressing papillomas consisted mainly of T cells stained by L11/135. It appeared that many dermal leukocytes (mainly T cells) form a non-cycling T cell population in both progressing and regressing papillomas, whereas intraepidermal T cells in regressing papillomas were effectively activated and represented a cycling T cell population. MAb-019 and Ki-67 MAbs demonstrated similar staining patterns in papilloma and normal tissues. However, in both progressing and regressing papillomas, the Ki-67 MAb usually stained a larger percentage of cells than the MAb-019 MAb. MAb-019 and Ki-67 MAbs showed a homogeneous distribution of positive cells from basal layer to the upper layer in progressing papillomas. On the other hand, in regressing papillomas, cell staining with the two antibodies was concentrated in the basal and lower layers, but not in the upper layers. This result indicates that cell proliferation in the upper epidermal layers is suppressed in regressing papillomas. Our present data show that intraepidermal T- cell activation and suppression of tumor proliferation might play a crucial role in papilloma regression.