Objective The objective of the study was to compare 9 cervical cancer screening strategies to the current screening standard (cytology with human papillomavirus HPV triage of atypical squamous cells of undetermined significance) for the detection of high-grade cervical disease. Study Design Women (n = 34,254) aged 30 years or older from the Addressing the Need for Advanced HPV Diagnostics (ATHENA) study underwent screening with cytology and HPV testing with simultaneous HPV16/18 genotyping; those with atypical squamous cells of undetermined significance cytology or greater or HPV-positive status were referred for colposcopy. Results In general, screening strategies that offered greater sensitivity also required more referral to colposcopy. HPV testing was more sensitive than cytology for detection of cervical intraepithelial neoplasia grade 2 or greater, but strategies that depended on cytology for triage of HPV-positive women decreased this sensitivity. Various strategies of cotesting with cytology increased sensitivity but did so by increasing testing. Strategies that included integrated HPV16/18 testing provided more efficient referral to colposcopy. Conclusion Strategies that maximize detection of women at greatest risk of cervical intraepithelial neoplasia grade 3 or greater by immediate referral to colposcopy, with follow-up testing of women at intermediate risk, maximize the benefits of cervical cancer screening while decreasing the potential harm. Incorporating screening with HPV and triage of HPV-positive women by a combination of genotyping for HPV16/18 and cytology provided a good balance between maximizing sensitivity (benefit) and specificity by limiting the number of colposcopies (potential harm).