PAX8 is a nephric-lineage transcription factor and is a crucial transcription factor for organogenesis of the thyroid gland, kidney, and Müllerian system. PAX8 is shown to be expressed in a high percentage of kidney and ovarian carcinomas. Limited information is known about the specificity of PAX8 in various neoplastic tumors. This comprehensive study examines the immuno-histochemical expression of PAX8 in multiple normal and neoplastic tissues including renal cell carcinoma and ovarian cancers. Renal cell carcinomas stained positive for PAX8 in 90% (110 of 122) of the cases and 100% of normal kidney stained PAX8 positive. In all cases of ovarian cancers 79% (181 of 229) expressed PAX8, and in thyroid cancer, PAX8 was expressed in 90% (9 of 10) cases. In endometrial cancers, 84% (113 of 134) of the cases were positive and in cervical cancer, 98% (1 of 60) squamous cell carcinomas cases were negative and 83% (5 of 6) cervical adenocarcinomas were positive. In bladder cancers, 93% of all the cases were negative including all bladder adenocarcinomas. PAX8 expression was observed in only one case of lung cancer (99% negative) and was 100% negative in cancers of the colon, breast, prostate, liver, testicular, stomach, esophagus, melanoma, gastrointestinal stromal tumors, leiomyosarcoma, and pheochromocytoma. The PAX8 specificity has been demonstrated in over 1100 cases of normal and neoplastic tissues. PAX8 is a specific and sensitive marker for renal cell and ovarian carcinomas and should be a valuable addition to the histopathology laboratory.