The role of the TP53 gene in the development of inherited and sporadic pheochromocytomas and medullary thyroid carcinomas (MTC) has not been clarified because of conflicting reports and limitations in the assays used to detect mutations. To determine the frequency of TP53 alterations in these tumors, 22 pheochromocytomas and 29 MTCs were screened for loss of heterozygosity (LOH) on 17p with four markers. Single-strand-conformation-variant (SSCV) analysis of exons 4-9 of the TP53 gene was performed in 20 of the pheochromocytomas and in 22 of the MTCs. The expression of p53 was determined by immunohistochemistry in 19 pheochromocytomas and in 17 MTCs using two antibodies (D01 and D07) on frozen and paraffin-embedded tissues. Four of the 22 pheochromocytomas and none of the MTCs showed LOH on 17p. No mutations were detected in any of the tumors screened by SSCV analysis. Immunohistochemical staining of frozen and paraffin-embedded tumor sections did not show p53 overexpression in any of the tumors examined. Our findings indicate that mutations in the TP53 gene are an uncommon event in the tumorigenesis of pheochromocytomas and medullary thyroid carcinomas.