The present study describes hyper-phosphorylation of E7-oncoprotein of human papillomavirus (HPV) type 16 in epidermal keratinocytes. We found that highly phosphorylated E7-oncoprotein was present in epidermal keratinocytes but little in fibroblasts. The E7 oncoprotein contains serine residues (Ser-Ser-Glu-Glu-Glu) capable of being phosphorylated by casein kinase II (CK II). Extracts from various cell lines including human origins transformed by HPV 16 were examined for the casein kinase activity. The results showed that CK II activity was present at significantly high levels in keratinocytes but little or no detectable levels of the activity in human fibroblasts. These differential CK II activities in host cells may play a part in the differential transforming activity by E7-oncoprotein.