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We compared the performance of the ThinPrep (TP) Imaging System (TIS) with manual reading of TP slides (TPM) and with manual reading of the paired conventional Pap smear (PS) in terms of sensitivity for and positive predictive value (PPV) of high-grade disease and productivity.The study consisted of 11,416 routine PS and paired TP slides as well as 103 confirmed abnormal TP slides.In terms of sensitivity for the detection of biopsy-confirmed high-grade disease, overall there was no statistically significant difference between TIS-screened TP (TPI) and TPM (81.1% vs. 86.8%). For the routine cases, TPI was significantly more sensitive than PS (73.4% vs. 57.8%).In terms of PPVs for the cytologic prediction of high-grade disease, there was no statistically, significant difference among TPI, TPM, and PS (75.6%, 73.9%, and 84.6%). For cytologic reports of possible high-grade disease, the PPVs were equivalent for TPI (45.0%) and TPM (37.0%) and there was no significant difference in PPVs between TPI and PS (61.3%). For TP slides, TIS screening showed a 27% productivity gain when compared with manual screening and a 54% productivity gain when compared with manual screening of PS slides.Use of TIS showed productivity benefits when compared with TPM and both productivity and sensitivity benefits over use of PS.