In a study involving 13,842 women and 113 gynaecologists, liquid-based cytology and HPV testing for detecting cervical cancer were compared. A total of 1334 women were found to be positive for one or both tests and were invited for colposcopy with biopsy. A total of 1031 satisfactory biopsies on 1031 women were thereafter collected using a systematic biopsy protocol, which was random in the colposcopically normal-appearing cervix or directed in the abnormal one. In all, 502 women with negative tests were also biopsied. A total of 82 histologic high-grade squamous intraepithelial lesion (HSIL) were reported in biopsies, all from the group with one or both tests positive. Sensitivity and specificity to detect histologic HSIL were 59 and 97% for cytology, and 97 and 92% for HPV. In total, 14% of reviewed negative cytological preparations associated with histologic HSIL contained no morphologically abnormal cells despite a positive HPV test. This suggested a theoretical limit for cytology sensitivity. HPV viral load analysis of the 1143 HPV-positive samples showed a direct relationship between abnormal Pap test frequency and HPV viral load. Thus, not only does the HPV testing have a greater sensitivity than cytology but the probability of the latter being positive can also be defined as a function of the associated HPV viral load.