Retroperitoneal recurrence of clear cell renal cell carcinoma (CCRCC) after surgical resection is often investigated by needle biopsy and frequently requires immunohistochemistry to distinguish from other lesions with similar histology. This study explores the diagnostic utility of a panel of immunohistochemical markers and emphasizes potential pitfalls in dealing with this differential diagnosis. A tissue microarray with 1 mm tissue cores was constructed to include 21 CCRCC, 19 adrenocortical lesions, and 15 retroperitoneal or mediastinal paragangliomas. Triplicate cores were used for each case. The tissue microarray was then immunostained with epithelial, RCC, adrenocortical, and neuroendocrine markers. Pancytokeratins AE1/3, CAM5.2, and epithelial membrane antigen were positive in 52.4%, 66.7%, and 61.9% of CCRCC cases. Three (14.2%) CCRCC cases were negative for all 3 epithelial markers. AE1/3 and epithelial membrane antigen were negative in all adrenocortical lesions and paraganglioma cases, whereas CAM5.2 was positive in 78.9% of adrenocortical lesions and 6.7% of paragangliomas. RCC markers, including RCC Ag, CA9, and CD10, were positive in 76.2%, 85.7%, and 100% of CCRCC cases and were negative in all adrenocortical lesions and paragangliomas. Calretinin and Melan-A were positive in 100% and 94.7% of adrenal, 0% and 14.3% of CCRCC, and 26.7% and 26.7% of paragangliomas. Epithelial markers may be entirely negative in CCRCC, whereas pancytokeratin CAM5.2 is often positive in adrenocortical lesions. Furthermore, neuroendocrine markers are frequently positive in adrenocortical lesions. Therefore, a panel of, rather than single, epithelial, "CCRCC-specific," adrenocortical and neuroendocrine markers should be applied in the differential diagnosis of CCRCC, adrenocortical lesions, and paragangliomas.