Abstract Type 18 human papillomavirus (HPV18) is a genital virus closely associated with cervical carcinoma. To analyze the transcriptional activities of the long control region (LCR) of the HPV18 genome, we have produced 12 transgenic mice harboring the HPV18/LCR sequence fused to a promoterless SV40 T-antigen (TAg) gene. The mice were small in body size, generally very weak, and none lived longer than 110 days. Three mice with the longest life span (58–110 days) developed hyperplastic thymus and/or lymph node and were further analyzed. In these mice, Northern hybridization failed to detect TAg transcripts in any of the 25 organs studied. However, spliced TAg RNA was detected by polymerase chain reaction in the hyperplastic thymus and lymph node and in the normal submaxillary gland, stomach, large intestine, urinary bladder, and the cerebrum, indicating the presence of very low cellular levels of TAg RNA in these organs. When immunostaining was performed on the hyperplastic thymus, TAg protein was detected only in the ductal epithelial cells. Our results appear to indicate that the HPV18/LCR sequence was able to express only unregulated and basal levels of transcriptional activity in transgenic mice. Such a mode of transcription has become a major hindrance in the use of transgenic mouse system for the studies of the biology of the human papillomavirus.