Several studies have suggested that p53 immunostaining does not occur in benign mesothelium but is common in malignancies involving the serous surfaces, including malignant mesothelioma. As a result, p53 has been advocated as a marker of malignancy in serous fluid cytology. However, the specificity of p53 in this context has been brought into question by some studies that claim to have found immunostaining in benign mesothelium. The aim of our study was to examine p53 immunostaining in a large series of serous fluids to try to resolve the uncertainty. Monoclonal Do-7 antibody was used to immunostain ethanol-fixed cytospin preparations employing an alkaline phosphatase method. Positivity was found in 17 of 35 malignant effusions, including two probable mesotheliomas, but was not found in any of 115 benign effusions. Our study suggests that p53 immunostaining is a highly specific and moderately sensitive marker of malignancy in serous fluids.