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Objectives Paired box protein-8 (PAX-8) immunohistochemical expression can be used as a diagnostic marker for epithelial cells tumors. This study aimed at investigating the immunohistochemical expression of PAX-8 among Sudanese females diagnosed with cervical, endometrial, and ovarian cancers between December 2017 and May 2019 by studying their Formalin-fixed paraffin embedded blocks. Results Sixty patients diagnosed with female reproductive tract cancers were included who aged 58.7 ± 6.9 years (range, 43—71). Cervix was the most common cancer site in 51/60 (85%) patients. Regarding cancer stage, there was 17 (28%) and 14 (23%) of the study population had stage 3B and 2B, respectively. The histopathological diagnosis included 20 (44%), 13 (29%), and 12 (27%) poorly, moderately, and well differentiated cervical squamous cell carcinoma (SCC) as well as 11 (73%), 2 (13%), 1 (7%), and 1 (7%) endometrial adenocarcinoma, metastatic adenocarcinoma, endocervical adenocarcinoma, and ovarian mucinous cyst adenocarcinoma, respectively. PAX-8 was positively expressed in 9 endometrial adenocarcinoma, 1 endocervical adenocarcinoma and 1 ovarian mucinous cyst adenocarcinoma, 2 poorly, and 1 moderately differentiated SCC. All patients diagnosed with well differentiated SCC and metastatic adenocarcinoma showed no expression of PAX-8. A statistically significant was seen for PAX-8 expression and the different histopathological diagnosis, P value < 0.001.