Liquid-based cytology (LBC) has replaced conventional cytology (CC) for cervical cancer screening in some countries. However, it remains unclear whether LBC is superior to CC. A randomized controlled trial was conducted between August 2007 and March 2009 in Germany to compare LBC, alone and in combination with computer-assisted imaging technology (CAS), to CC in the detection of histologically confirmed cervical intraepithelial neoplasia (CIN). The main outcome measures were detection rates, relative sensitivities, positive predictive values (PPVs) and relative PPVs comparing LBC without and with CAS to CC. Primary histological outcome was CIN2 or higher. Included were 20,627 women participating in opportunistic cervical cancer screening at 20 gynecologic practices. The practices were randomized weekly to use LBC (n 5 11,331) or CC (n 5 9,296). Patients with positive findings were invited to expert colposcopy. The relative sensitivity of LBC versus CC using the CIN21 cut-off was 2.74 (95% confidence interval [CI] 1.66-4.53). The relative sensitivity of LBC/CAS versus CC for CIN21 was 3.17 (95% CI 1. 94-5.19). The PPV of LBC and CC for CIN21 was 48% and 38%, respectively. The PPV ratio did not differ significantly from unity. Differences between LBC and CC were smaller in some sensitivity and subgroup analyses; however, relative sensitivity of LBC remained increased. LBC without and with CAS compared with CC under the field conditions of an opportunistic screening system had a significantly higher sensitivity for the detection of CIN without deterioration of PPVs. Additional use of CAS did not further improve sensitivity of LBC. V C 2012 Wiley Periodicals, Inc.Key words: randomized controlled trial, early detection of cancer, uterine cervical neoplasm, Papanicolaou smear, liquid-based cytology, computer-assisted imaging technology Additional Supporting Information may be found in the online version of this article. Stefanie J. Klug, Jochem K€ onig and Hans Ikenberg had full access to all the data of the study. They take responsibility for the integrity of the data and the accuracy of the data analysis. Hans Ikenberg, Stefanie J. Klug, Klaus J. Neis and Werner Harlfinger take responsibility for the study concept and design. Werner Harlfinger and Klaus J. Neis take responsibility for the acquisition of data. Stefanie J. Klug, Jochem K€ onig, Veronika Weyer and Hans Ikenberg take responsibility for the analysis and interpretation of data. Stefanie J. Klug and Hans Ikenberg take responsibility for the drafting of the manuscript. All are responsible for the critical revision of the manuscript for important intellectual content. Jochem K€ onig, Veronika Weyer and Stefanie J. Klug did the statistical analysis. Werner Harlfinger, Klaus J. Neis, Armin Malter and Hans Ikenberg obtained funding. Sibylle Spieth, Friederike Brinkmann-Smetanay and Friedrich Kommoss had the administrative, technical or material support. Study supervision is by Hans Ikenberg, Werner Harlfinger, Klaus J. Neis and Stefanie J. Klug. Stefanie J. Klu...