New screening guidelines recommend that human papillomavirus (HPV)-negative/atypical squamous cells of undetermined significance (ASC-US) results be considered as equivalent to HPV-negative/Pap-negative results, leading to rescreening in 5 years. However, despite ample data, the routine clinical performance of HPV testing of women with ASC-US has not been adequately documented. We estimated 5-year risks of cervical intraepithelial neoplasia (CIN) 3+ and of cancer among 2 groups of women between 2003 and 2010 at Kaiser Permanente Northern California: 27,050 aged 30 to 64 years who underwent HPV and Pap cotesting and had an ASC-US Pap result and 12,209 aged 25 to 29 years who underwent HPV triage of ASC-US. Five-year risks of CIN 3+ and of cancer among women aged 30 to 64 years testing HPV-negative/ASC-US and among 923,152 women testing Pap-negative alone were similar although statistically distinguishable (CIN 3+, 0.43% vs 0.26%, p = .001; cancer, 0.050% vs 0.025%, p = .1). The increased risk of cancer after HPV-negative/ASC-US versus Pap-negative alone was confined to women aged 60 to 64 years (0.26% vs 0.035%, p = .3). Five-year risks of CIN 3+ and cancer among women with HPV-negative/ASC-US results were substantially higher than those among women testing HPV-negative/Pap-negative (CIN 3+, 0.43% vs 0.08%, p < .0001; cancer, 0.050% vs 0.011%, p = .003). For women aged 30 to 64 years testing HPV-positive/ASC-US, 5-year risks of CIN 3+ and cancer were slightly higher than those among 9,374 women with low-grade squamous intraepithelial lesion (LSIL) (CIN 3+, 6.8% vs 5.2%, p = .0007; cancer, 0.41% vs 0.16%, p = .04). Similar patterns were seen for women aged 25 to 29 years. Women with HPV-negative/ASC-US had a similar risk as women testing Pap-negative alone but had a higher risk than women testing HPV-negative/Pap-negative. Based upon the principle of "equal management of equal risks," our findings support the equal management of women with HPV-negative/ASC-US and those with Pap-negative alone, except for exiting women from screening because cancer risks at ages 60 to 64 years may be higher for women testing HPV-negative/ASC-US. Our findings also support managing HPV-positive/ASC-US and LSIL similarly.