The recognition of high-risk human papillomaviruses (HPVs) as etiological agents of cervical cancer has increased the demands to use testing for HPV for the detection of abnormal cervical smears and for cervical cancer screening. The present study compared the performance of the Hybrid Capture 2 (HC2) assay with that of PCR for the detection of significant cervical lesions in 1,511 women with different risks for HPV infections in three New Independent States of the former Soviet Union. The results showed that the level of agreement between the HC2 assay and PCR was substantial, with a kappa (Cohen) value of 0.669 (95% confidence interval [CI], 0.629 to 0.709). Of the 228 samples with discrepant results, 92 were positive by the HC2 assay but negative by PCR, whereas 136 samples were PCR positive but HC2 assay negative. The positive predictive values (PPVs) of the HC2 assay and PCR in detecting high-grade intraepithelial lesions (HSILs) were 4.5% (95% CI, 3.5 to 5.5%) and 3.6% (95% CI, 2.7 to 4.5%), respectively, and the negative predictive values (NPVs) were 99.6% (95% CI, 99.3 to 99.9%) and 99.3% (95% CI, 98.9 to 99.7%), respectively. The sensitivities of the HC2 assay and PCR for the detection of HSILs were 85.2 and 74.0%, respectively, and the specificities were 67.2 and 64.1%, respectively. In receiver operating characteristic (ROC) analysis, the performance of the HC2 assay for the detection of HSILs was excellent (P ؍ 0.0001); the area under the ROC analysis curve was 0.858 (95% CI, 0.811 to 0.905), and the optimal balance between sensitivity (86.5%) and specificity (80%) was obtained with an HC2 assay cutoff level of 15.6 relative light units/positive control. Use of this cutoff would increase the specificity of the HC2 assay to 80.0% without compromising sensitivity. In conclusion, the results of PCR and the HC2 assay were concordant for 85% of samples, resulting in substantial reproducibility. Both tests had low PPVs, equal specificities, and equal (almost 100%) NPVs for the detection of HSILs; but the sensitivity of the HC2 assay was slightly better.Cervical carcinoma is the second most common malignancy in women worldwide. Infection with high-risk (HR) types of human papillomaviruses (HPVs) is the single most important risk factor for cervical cancer and its precursors (27,29). Screening for cervical cancer is traditionally based on Pap smear cytology, which suffers from subjectivity and which depends on the skills of the observer. The Pap test usually shows variable (poor to moderate) sensitivities (30 to 87%), and equivocal cases need to be repeated to improve diagnostics (4, 13). The recognition of HR HPVs as etiological agents of cervical cancer has increased the demands to use testing for HPV for the diagnosis of abnormal cervical smears (11) and even for screening for cervical cancer (9, 18). Testing for HPV has been shown to have higher sensitivities (84 to 100%) than the conventional Pap smear. Also, the negative predictive value (NPV) of testing for HPV DNA is very high; Clavel et al.(1) rep...