Our study directly compares the performance of liquid-based (LBC) and conventional cytology for detecting high-grade cervical intraepithelial neoplasia and cancer (CIN 21) in high-risk, previously unscreened women. As part of a larger randomized clinical trial assessing the efficacy and safety of a ''screen and treat'' program for cervical cancer prevention, 5,652 South African women, aged 35 to 65 years, were screened using either ThinPrep or conventional Papanicolaou cytology. The cytology method used (i.e., ThinPrep or conventional) was rotated on a 6-month basis for the duration of the study. Directly following collection of the cytology specimen, all women underwent colposcopy with endocervical curettage and biopsy of all colposcopic abnormalities. Assessment of cytology and histology results was blinded and results were compared using histology-confirmed CIN as the ''gold standard.'' The accuracy of LBC and conventional cytology was statistically equivalent, although the sensitivity of conventional cytology was at least 5 percentage points higher at all cutoff levels. For example, at a cytology cutoff level of low-grade squamous intraepithelial lesion, the sensitivity of LBC was 60.3% for CIN21 vs. 69.1% for conventional cytology and specificity was 94.1% and 94.5%, respectively. LBC specimens were significantly less likely to be ''satisfactory-but-limited-by'' (6.5% vs. 27.9%) but significantly more likely to be unsatisfactory (2.2% vs. 0.8%). Thus, in this high-risk population, the sensitivity of LBC is no greater than the sensitivity of conventional cytology. Because of the higher unit cost of LBC, low resource settings should carefully consider the potential benefits and drawbacks of LBC before adopting this new technology. ' 2005 Wiley-Liss, Inc.Key words: cervical cytology; papanicolaou (Pap) smear; liquidbased cytology; cervical intraepithelial neoplasia Conventional cytology, i.e., the Papanicolaou smear, has been the mainstay of cervical cancer screening since the 1960s and is credited with successfully reducing the incidence and mortality of invasive cervical cancer in many developed countries. 1,2 Nonetheless, the accuracy of this important screening tool remains controversial, with several large meta-analyses suggesting that both the sensitivity and specificity of cervical cytology is relatively low (30% to 87% sensitivity, 86% to 100% specificity). [3][4][5] As an alternative to conventional cytology, liquid based-cytology (LBC) was introduced in the mid-1990s. The purported advantages of LBC include a possible increase in the detection of high-grade cervical intraepithelial neoplasia (CIN 2,3 ), a reduction in the number of unsatisfactory and ''satisfactory-but-limited-by'' specimens, and providing residual cellular material for subsequent molecular testing (e.g., testing for ''high-risk'' types of HPV DNA). On the other hand, the unit cost of LBC methods is substantially more than that of conventional cytology. The substantial increase in unit cost is of particular concern in less-developed...