Immunohistochemistry (IHC) is an important adjunctive test in diagnostic surgical pathology. We studied the clinical significance and outcomes in performing IHC on cases with a previous diagnosis of cancer who are coming to the Fox Chase Cancer Center (FCCC), a National Cancer Institute designated National Comprehensive Cancer Center (NCCC), for treatment and/or second opinion. We reviewed all the outside surgical pathology slide review cases seen at the FCCC for 1998 and 1999 in which IHC was performed. Cases were divided into the following: confirmation of outside diagnoses without and with prior IHC performed by the outside institution (groups A and B, respectively) and cases with a significant change in diagnosis without and with prior IHC performed by the outside institution (groups C and D, respectively). During 1998 and 1999, 6678 slide review cases were reviewed at the FCCC with an overall significant change in diagnosis in 213 cases (3.2%). IHC was performed on 186 of 6678 (2.7%) slide review cases with confirmation of the outside diagnosis in 152 (81.7%) cases and a significant change in diagnosis in 34 (18.3%) cases. Patient follow-up was obtained in 32 of 34 (94.1%) cases with a significant change in diagnosis (groups C and D), which confirmed the correctness of our diagnosis in 26 of 27 cases (96%; in five cases follow-up was inconclusive). We repeated the identical antibodies performed by the outside institutions in group D (37 antibodies) and group B (133 antibodies) with different results in 48.6% and 13.5%, respectively (overall nonconcordance 21.2%). In group D additional antibody tests beyond that performed by the outside institution were needed in 88.8% of cases to make a change of diagnosis. In the setting of a NCCC, reperforming and/or performing IHC on cases with a previous diagnosis of cancer is not a duplication of effort or misuse of resources. Repeating and/or performing IHC in this setting is important in the care and management of patients with cancer.