Experimental and observational evidence suggests that chronic hypoxic stimulation can induce parasympathetic paraganglioma. This is emphasized by the identification of germline mutations in genes of the mitochondrial succinate dehydrogenase enzyme complex II in hereditary paraganglioma. Because of inactivating mutations in the succinate dehydrogenase subunit B (SDHB), C (SDHC), or D (SDHD) gene, the paraganglia undergo a chronic hypoxic stimulus leading to proliferation of the paraganglionic cells. Hypoxia is a known inducer of p53 up-regulation, which triggers cell cycle arrest and apoptosis. Inactivation of the p53 pathway, by gene mutation or by MDM2 overexpression, would enable cells to escape from cell cycle arrest and apoptosis and could contribute to tumorigenesis. To determine whether p53 inactivation plays a role in paraganglioma tumorigenesis, we investigated a series of 43 paragangliomas from 41 patients (of whom 24 patients harbored a germline SDHD mutation) for mutations in p53 exons 5-8 by PCR-SSCP. In addition, these tumors were investigated for p53 and MDM2 protein expression by immunohistochemistry, and the results were compared with clinical data and the presence of SDHD mutations. No aberrations in p53 exons 5-8 were found. The immunohistochemical experiments showed nuclear p53 expression in 15 tumors. Three tumors were positive for MDM2 that were also positive for p53. There was no correlation between p53 and MDM2 expression and clinical data or SDHD status. Given the fact that hypoxia induces p53 expression and regarding the absence of p53 mutations, these results suggest that p53 inactivation does not play a major role in the tumorigenesis of hereditary and sporadic paragangliomas.