Our objective was to determine whether the addition of human papillomavirus (HPV) testing to screening cytology improves the detection of cervical cancer precursors. Women of ages 18-69 years underwent conventional Pap cytology and HPV DNA testing in a multicenter study in Newfoundland, Canada. Those with positive cytology and/or HPV and a random sample of those with dual negative results were referred for colposcopy. The study enrolled 2098 women. The relative sensitivity of HPV testing was significantly higher than cytology for all-grade squamous intraepithelial lesions [SILs; 73%; 95% confidence interval (CI), 62-82] and high grade SILs (HSILs; 90%; 95% CI, 74-97) but had lower relative specificity (62% for all-grade SILs and 51% for HSILs) than most cytological cutpoints. The rate of combined correct results for all-grade lesions was higher for HPV testing (68.8%) than for any cytological cutpoint (equivocal, 52.3%; LSILs, 51.6%; HSILs, 44.5%). The combination of HPV and an LSIL cutpoint had a negative predictive value of 68% (95% CI, 52-80) for all SILs and 100% (95% CI, 91-100) for HSILs, while referring for colposcopy only 12% of the women. We concluded that HPV testing in conjunction with cytology improved the screening efficacy of cytology alone and may allow for a more effective and safe primary screening program with increased screening intervals.