Human-papillomavirus (HPV) DNA testing has been proposed as an alternative to primary cervical cancer screening using cytological testing. Review of the evidence shows that available data are conflicting for some aspects. The overall goal of the study is to update the performance of HPV-DNA as stand-alone testing in primary cervical cancer screening, focusing particularly on the aspects related to the specificity profile of the HPV-DNA testing in respect to cytology. We performed a meta-analysis of randomized controlled clinical trials. 8 articles were included in the meta-analysis. Three outcomes have been investigated: relative detection, relative specificity, and relative positive predictive value (PPV) of HPV-DNA testing versus cytology. Overall evaluation of relative detection showed a significantly higher detection of CIN2+ and CIN3+ for HPV-DNA testing versus cytology. Meta-analyses that considered all age groups showed a relative specificity that favored the cytology in detecting both CIN2+ and CIN3+ lesions whereas, in the ≥30 years group, specificity of HPV-DNA and cytology tests was similar in detecting both CIN2+ and CIN3+ lesions. Results of the pooled analysis on relative PPV showed a not significantly lower PPV of HPV-DNA test over cytology. A main key finding of the study is that in women aged ≥30, has been found an almost overlapping specificity between the two screening tests in detecting CIN2 and above-grade lesions. Therefore, primary screening of cervical cancer by HPV-DNA testing appears to offer the right balance between maximum detection of CIN2+ and adequate specificity, if performed in the age group ≥30 years © 2013 Wiley Periodicals, Inc.