Human papillomavirus (HPV) testing is more sensitive for the detection of cervical precancer and cancer than cervical cytology. The increased sensitivity of HPV testing and cytology combined ("cotesting") compared to cytology alone permitted professional societies to recommend 3-year screening intervals among the cotest-negative results. However, there is an increasing recognition that both clinical sensitivity and specificity of cervical cancer screening are important to patient safety and must be considered in the context of using current and future HPV DNA tests. Exquisite analytic sensitivity for HPV does not increase clinical sensitivity of an HPV test but does result in excessive test positivity and decreased clinical specificity. A recent US Food and Drug Administration (FDA)-approved HPV test, Cervista (Hologic, Bedford, MA), demonstrated excessive test positivity-2 to 4 times more positive than the other FDA-approved HPV test-from its premarketing approval trial. The poor specificity of Cervista raises questions about the safety and applicability of using this test in routine cervical cancer screening. These data provide a didactic example of the potential dangers of mistaking excellent analytic sensitivity and even clinical sensitivity for good clinical performance.