INTRODUCTION: Advancements in digital imaging technology for Papanicolaou test slides, combined with artificial intelligence are driving the development and adoption of innovative computer-assisted screening methods for cervical cancer within the cytology community. Our study aimed to assess the performance of the Hologic Genius Digital Diagnostic System (HGDDS) in the interpretation of low-grade squamous intraepithelial lesions (LSIL) in ThinPrep Papanicolaou slides. METHOD: As part of a validation study performed with 890 ThinPrep Papanicolaou slides using the HGDDS, a subset of 146 LSIL cases were included in this study. Performance characteristics for the detection of cervical intraepithelial neoplasia (CIN) and interobserver variability among 3 cytopathologists were assessed. RESULTS: On evaluation of the consensus results of the 3 cytopathologists, of the 146 LSIL Papanicolaou cases, 60.3% were interpreted as LSIL with the HGDDS. The remainder were interpreted as ASCUS (26%), ASC-H (10.3%), HSIL (2.7%), and NILM (0.7%). The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for detecting CIN1+ lesions in the ASCUS + category with the HGDDS were 100%, 25%, 97.9%, and 100%, respectively. The sensitivity, specificity, PPV, and NPV for the detection of CIN1+ lesions in the LSIL + category with the HGDDS were 74.7%, 75%, 99.1%, and 7.7%, respectively. Kendall's W coefficient was 0.792, indicating strong agreement among participating pathologists. CONCLUSIONS: Our study demonstrated that ThinPrep Papanicolaou tests with LSIL could be interpreted with strong agreement among pathologists and with good performance indicators when utilizing the HGDDS.