Schwannomas have been variably observed to be glial fibrillary acid protein (GFAP) and occasionally keratin positive, with antibodies reacting with multiple keratins (pankeratins, keratin cocktail (CK), but specific keratin polypeptides (K) have not been examined for in schwannoma. Since we observed CK positivity in retroperitoneal schwannomas, we wanted to study a large group of retroperitoneal and peripheral schwannomas with GFAP, CK and Ks to explore the frequency and biologic background of this finding. We immunohistochemically evaluated a large number of retroperitoneal (n=115) and peripheral schwannomas (n=22) for GFAP, 16 individual K and AE1/AE3 keratin cocktail. The great majority (104/115, 90%) of retroperitoneal schwannomas were positive for GFAP, and 72/104 (69%) cases were positive for AE1/AE3, often extensively. Both markers highlighted the cellular Antoni A areas, particularly adjacent to the capsule, myxoid or degenerative areas, and perivascularly. Most cases 87/104 (84%) stained for both AE1/AE3 and GFAP at least focally. No tumors stained for keratins that were GFAP negative. None of the immunostains for individual K showed positivity comparable to that obtained with AE1/AE3 CK. However, 62% were focally positive for high molecular weight K1 and 8/61 (13%) for K7. None of the retroperitoneal schwannomas were positive for other keratins including K2, 4, 5, 8, 9, 10 and K14-20. Peripheral schwannomas showed GFAP-positivity in only three of 22 cases (14%), and all were negative for keratins, both cocktail and individual K. We conclude that crossreactivity of AE1/AE3 with other intermediate filament proteins, such as GFAP, as previously observed in brain and glioma tissue, probably accounts for the extensive keratin-positivity seen in some retroperitoneal schwannomas. However, focal expression of K1 and K7 cannot be ruled out. Keratin-positive schwannomas should not be confused with other keratin-positive tumors, such as sarcomatoid carcinoma, mesothelioma, and synovial sarcoma.