BACKGROUND: We investigated the impact of human papillomavirus (HPV) vaccination on the performance of cytology-based and HPV-based screening for detection of cervical precancer among women vaccinated as young adults and reaching screening age. METHODS: A total of 4632 women aged 25-36 years from the Costa Rica HPV Vaccine Trial were included (2418 HPV-vaccinated as young adults and 2214 unvaccinated). We assessed the performance of cytology- and HPV-based cervical screening modalities in vaccinated and unvaccinated women to detect high-grade cervical precancers diagnosed over 4 years and the absolute risk of cumulative cervical precancers by screening results at entry. RESULTS: We detected 95 cervical intraepithelial neoplasia grade 3 or worse (52 in unvaccinated and 43 in vaccinated women). HPV16/18/31/33/45 was predominant (69%) among unvaccinated participants, and HPV35/52/58/39/51/56/59/66/68 predominated (65%) among vaccinated participants. Sensitivity and specificity of cervical screening approaches were comparable between women vaccinated as young adults and unvaccinated women. Colposcopy referral rates were lower in the vaccinated group for HPV-based screening modalities, but the positive predictive value was comparable between the 2 groups. CONCLUSIONS: Among women approaching screening ages, vaccinated as young adults, and with a history of intensive screening, the expected reduction in the positive predictive value of HPV testing, associated with dropping prevalence of HPV-associated lesions, was not observed. This is likely due to the presence of high-grade lesions associated with nonvaccine HPV types, which may be less likely to progress to cancer.