This study was designed to optimize a liquid-based Papanicolaou (Pap) test by using common cytopathology laboratory equipment and resulted in an inexpensive test that was equivalent at least diagnostically to the conventional Papanicolaou (Pap) smear.Adult women (n = 482) were consented, enrolled, and included in this Institutional Review Board-approved study. After conventional Pap smear slides were obtained, clinicians placed the collection device with residual cells from the uterine cervix in a preservative fluid. In the cytopathology laboratory, a conventional centrifuge device was used to deposit the cells from the liquid onto a glass slide.Among the conventional Pap smears, 43 were categorized as low-grade squamous intraepithelial lesions (LSIL), and 30 were categorized as high-grade squamous intraepithelial lesions or greater (HSIL+). Among the PapSpin samples, 49 were categorized as LSIL and 24 were categorized as HSIL+. Biopsy confirmation was obtained in 124 patients. There were 23 women diagnosed with LSIL and 27 women diagnosed with HSIL+. Diagnostic agreement between cytologic samples and biopsies is as follows: for conventional Pap smears, there was agreement on 11 of 23 LSIL diagnoses and on 15 of 27 HSIL+ diagnoses; for PapSpin samples, there was agreement on 11 of 23 LSIL diagnoses and on 14 of 27 HSIL+ diagnoses. Exact agreement was achieved between PapSpin and conventional smears in 404 patients (84%). Quality indictors were better in the PapSpin group, except for inadequate endocervical component, which was greater in the PapSpin samples, a difference that was explained by the split-sample study design, which favored the conventional smear.The current results indicated that PapSpin is a legitimate, inexpensive alternative to the conventional Pap smear for the detection of cervical intraepithelial neoplasia, resulting in better preservation and improved cell visualization. In addition, the liquid residual allows for reflex human papillomavirus-DNA or polymerase chain reaction testing.