Background and Objective: The aim of this study was to compare the screening performance of a new modified liquid-based cytology method (Liquiprep™) with conventional PAP smear (CP) in a low risk population, using colposcopy followed by histology as “gold standard”. Patients and Methods: This cross-sectional study was performed on random referred specimens to a general gynecological clinic in Tehran, during 20 months by a split-sample method. In both CP and Liquiprep™ group, all positive and 10% of negative results of smears were followed by colposcopy. A biopsy was taken whenever any atypical transformation zone seen. Sensitivity, specificity, negative and positive predictive values (PV), and overall accuracy of both methods were analyzed in relation to histology. Results: A total of 1265 patients were analyzed by two methods. In 158 (12.5%) of cases histological diagnosis was made. Liquiprep™ samples (94.7%) were more adequate than CP (92.1%). There was not any low or high-grade squamous intraepithelial lesion (SIL). Atypical squamous cell of undetermined significance (ASC_US) was diagnosed more with CP than with Liquiprep™ (1.43% vs. 0.79%) while pathologically 60% of ASC_US in Liquiprep™ and 16.6% in CP had degrees of SIL. The Liquiprep™ had a significantly higher sensitivity (83% vs. 66%) and positive PV (83% vs. 33%) than the CP to detect SIL at histology but the difference in specificity was non significant (98% vs. 86%). Conclusions: This study confirms the superiority of the Liquiprep™ method to detect cervical lesions in a low risk population.