We evaluated a more efficient method of processing liquid-based cervical cytology specimens for human papillomavirus (HPV) DNA testing by Hybrid Capture II (HCII). Aliquots were made from 701 specimens in the following sequence: 4.0, 2.0, 1.0, 0.5, and 1.5 mL. The 4.0-mL aliquot was processed by the standard method (STP), and half of the processed material was tested by HCII. Other aliquots were processed with a new, filtration-based processing method (NPM). The 2.0-mL NPM aliquot had HCII test performance most similar to the STP, ie, similar HCII positivity (P = .4) and good test agreement (kappa = 0.85, 95% confidence interval [CI], 0.80-0.89). The 194 cytologic negatives had greater positivity by STP (P = .04) compared with the 2.0-mL aliquot processed by NPM; between-method agreement was modest (kappa = 0.54, 95% CI, 0.36-0.72). A lower positive cut point for the 2.0-mL NPM aliquot partially abrogated this minor difference. In 241 specimens diagnosed as low-grade and 31 as high-grade squamous intraepithelial lesions, there were no significant differences in HPVpositivity (>85% and 90%, respectively) between STP and NPM. NPM reduces specimen handling and decreases total testing time by approximately 33% without significant losses in HCII test performance.