Background: To evaluate the clinical significance of atypical squamous cells of undetermined significance (ASCUS) in PAP test in post-menopausal women and compare with pre -enopausal women. Methods: A total of 500 patients who referred to our gynecologic clinic in “ Mbreteresha Geraldine” Hospital, Tirane, Albania, were included to the study between January 2012 and August 2014. Data for 194 post-menopausal (group 1) and 306 pre-menopausal (group 2) women with ASCUS cytology were evaluated. Patients interventions: Immediate colposcopy and endocervical curettage was performed for both groups and conization for all women with a result suggestive of CIN2-3. HPV –DNA were assessed for all woman. Main outcome measures: Histopathological results and demographic features of patients were compared between the two groups. Results: Mean age of the patients was 54.6±6.5 years in group 1 and 38±6.6 years in group 2. Some 19 (9.4%) of post- menopausal women and 49 (15.9%) of pre-menopausal women were current smokers. No one was suffering from another disease. Totals of post-menopausal and pre-menopausal women were assessed for HPV-DNA. HPV –DNA testing was performed by polymerase chain reaction (PCR) with pU1M/pU2R primers in GENOMA Laboratory, Rome, Italy. High risk HPV was detected in 27 (14 %) and 85 (28 %), respectively (p=0.029). Final histopathological results recorded were normal cervix, low grade cervical intra-epithelial neoplasia (CIN 1), and high grade cervical intra-epithelial neoplasia (CIN2-3). In group 1, results were 84.8%, 12.2% and 1.8%, respectively, and in group 2 were 71.9%, 23.2% and 4.9%. Two cases were detected as micro-invasive carcinoma in pre-menopausal group (1%). Two cases were detected as endometrial carcinoma in the menopausal group (0.6 %). Conclusions: In current study we found that preinvasive lesions were statistically significantly higher in pre-menopausal women than post-menopausal women with ASCUS. High risk HPV were significantly higher in pre-menopausal women. Cervicitis was more common in menopausal women.