The accurate identification of suspicious cells in cytologic preparations is a common problem in diagnostic cytopathology. Recent studies have shown that mutation of the p53 gene may be the most common genetic event in human malignancy. Mutation leads to altered conformation and increased half-life of the p53 protein, resulting in detectability by immunocytochemistry. The usefulness of p53 immunocytochemical staining as a marker of malignancy in the cytologic analysis of body fluids was investigated in the present study. One hundred fifty-four serial samples of body fluids submitted for cytologic diagnosis were also examined for p53 immunoreactivity. Of 121 cases reported as cytologically benign, 3 (2.5%) stained positively for p53; 16 samples were cytologically malignant, and 7 (43.7%) of these were positive for p53 (P < .001). Of those reported as suspicious but not conclusively malignant, 4 of 17 (23.5%) showed p53 immunoreactivity. On review, two of the three patients whose samples were benign cytologically yet showed positive p53 staining had histologic evidence of malignancy. The third patient died without a postmortem examination. Of the 17 cytologically suspicious cases, 16 (94.1%) were later proven to be malignant, and p53 was positive in 4 (25%). These results suggest that p53 immunostaining could be of value as a marker of malignancy in the cytologic examination of body fluids. The presence of p53 immunoreactivity in cytologic samples is strongly suggestive of malignancy, though its absence does not exclude neoplasia.