To evaluate p53 immunostaining as a marker of malignancy in pleural and peritoneal effusions and to compare the results with HE staining. Pleural and peritoneal effusion samples were obtained from patients suffering from benign and malignant diseases. H&E staining and p53 immunostaining were performed on smears prepared from these samples. The samples were obtained from patients admitted in Mayo Hospital, Services Hospital, Gulab Devi Chest Hospital and Institute of Nuclear Medicine and Oncology (INMOL). One hundred cases having either pleural or peritoneal effusions were selected. Fifty of these cases were positive for malignant cells on H&E staining. Fifty cases contained only mesothelial cells. To compare the specificity and sensitivity of p53 immunostaining with HE stain as a diagnostic marker of malignancy. Out of the 50 malignant cases, 31 (62%) were found to be p53 positive. None of the benign cases showed positive staining. p53 was found to have a specificity of 100%, sensitivity of 62%, a positive predictive value of 100% and a negative predictive value of 72.4%. p53 is a highly specific and moderately sensitive marker of malignancy.