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We read with interest the article by Cotton et al1 but disagree with their conclusion. Rather, we believe that human papillomavirus (HPV) mRNA assays, when used in accord with U.S. Food and Drug Administration labeling, are appropriate for use as a first-line screening tool for cervical cancer because of their similar sensitivity and superior specificity. The authors' study did not contain clinical follow-up data and therefore could not address clinical sensitivity or specificity.1 Numerous larger, head-to-head comparisons found mRNA testing to have comparable sensitivity with DNA testing for high-risk lesions, with superior specificity, in screening and referral settings.2–4Our experience aligns with these larger studies. We analyzed deidentified findings from a nationwide sample of 34,640 women aged 30–65 years who had HPV mRNA (n=19,228) or DNA (n=15,412) testing (based on clinician preference) followed by colposcopy–biopsy within 6 months (data on file). High-grade disease (cervical intraepithelial neoplasia [CIN] 3 or worse) was found in 714 women; 73 had cancer. The methods did not differ in sensitivity for CIN 3 or worse (HPV mRNA, 98.5%; HPV DNA, 97.1%; P=.4), but HPV mRNA testing was more specific (19.4% vs 13.4%; P<.001) for high-risk lesions.These findings and previous work2–4 support the conclusion that HPV mRNA testing has comparable sensitivity with HPV DNA, with greater specificity.