Since cervical cancer remains common in Mexico despite an established cytology screening program, the Ministry of Health recently introduced pilot front-line HPV testing into the Mexican cervical cancer screening program (CCSP). Here, we present the key field performance metrics of this population-based study. High-risk HPV DNA (hrHPV) testing was conducted on self-collected vaginal specimens from 100,242 women aged 25–75 years residing in Morelos State. All hrHPV positive women and a random sample of 3.2% (n = 2,864) of hrHPV negative participants were referred for colposcopic examination. The main disease endpoint of interest was cervical intraepithelial neoplasia grade 2 or higher (CIN2+). We calculated relative risk, positive predictive value and negative predictive value adjusted for screening test verification bias. The overall prevalence of hrHPV was 10.8% (95%CI 10.6–11.0). Women positive for hrHPV had a relative risk of 15.7 for histologically detectable CIN2+. The adjusted positive predictive value of the hrHPV test was 2.4% (95%CI 2.1–2.7); whereas the adjusted negative predictive value was 99.8% (95%CI 99.8–99.9). These findings suggest that large-scale vaginal hrHPV testing in a middle-income country can identify women at greater risk of advanced cervical abnormalities in a programmatically meaningful way but care is warranted to ensure that disease not detectable at colposcopy is kept to a minimum. PASS shows areas that need improvement and sets the stage for wider use of hrHPV screening of self-collected vaginal specimens in Mexico.