Recently updated cervical screening guidelines have proposed a 5-year screening interval for women aged 30 years and older with "double-negative" Papanicolaou (Pap) and high-risk human papillomavirus (hrHPV) results (DNR); however, published US follow-up data on women with DNR tested with US Food and Drug Administration (FDA) - approved HPV testing are limited to studies from Kaiser Permanente using conventional Pap smear cytology. Between July 2005 and June 2006, 4,112 patients with DNR who were screened with computer-imaged liquid-based cytology (LBC) (ThinPrep) and Hybrid Capture 2 (HC2) hrHPV tests of LBC vial fluid were identified. Cytologic or histopathologic data were available for 3,211 patients who were followed up for a mean 44 months. Among 2,960 patients aged 30 years and older with DNR, follow-up cervical abnormalities of cervical intraepithelial neoplasia (CIN) 3 or more severe (CIN3+) were documented in 5 (0.17%), including 1 endocervical adenocarcinoma. After DNR, CIN+ diagnoses were significantly more likely in women younger than 50 years than in older women. These data are consistent with previously published US and international studies that have consistently documented low rates of histopathologic CIN3+ during years of follow-up after DNR. Large-scale nationwide data are needed to further assess the level of risk of invasive cervical cancer after DNR using different available hrHPV testing methods.