The tumour suppressor gene p53 is frequently mutated in neoplasia. Since mutant p53 protein is often over-expressed, mutation can be indirectly detected by immunocytochemical techniques. As microwave antigen retrieval is becoming a widespread method for increasing the antigenicity of paraffin sections, we investigated the application of this technique to p53 immunohistochemical staining of oral mucosa specimens. Paraffin sections of 22 squamous cell carcinomas (SCC) and 36 benign lesions were immunohistochemically stained with and without antigen retrieval. Without antigen retrieval p53 over-expression was observed in 6/22 SCC and 1/36 benign lesions. Following antigen retrieval positive staining was observed in 15/22 SCC and 35/36 benign lesions. Staining in benign lesions was confined to basal and parabasal cells and could reflect normal functioning of wild-type p53. We conclude that antigen retrieval increases the sensitivity of p53 immunoreactivity, but such staining is not specific for malignancy and should be interpreted with caution.