We used modeling approaches to estimate the impact of human papillomavirus (HPV) vaccination on the performance of Pap cytology screening under different assumptions of lesion prevalence and expected changes in sensitivity and specificity likely to prevail post-vaccination. A major driver of the efficiency and costs of screening, the positive predictive value will be severely affected if Pap cytology continues to serve as the primary screening test in the post-vaccination era. Molecular-based screening with an HPV DNA test followed by Pap triage of HPV-positive cases has the potential for circumventing this problem. As a primary screening test, HPV testing can improve the overall quality of screening programs, thus allowing for increased testing intervals that would lower program costs with acceptable safety. Cytology should be reserved for the more labor-efficient task of triaging HPV-positive cases, a situation in which case loads would be "enriched" with smears containing relevant abnormalities. HPV followed by Pap strategy can also serve a secondary role in post-vaccination surveillance.