Inflammatory pseudotumor (IPT) of the lung is a non-neoplastic process that consists of proliferating spindle cells (fibroblasts and myoblasts), with variable numbers of mitoses, and inflammatory cells, particularly plasma cells. These lesions clinically, radiographically, and grossly mimic malignant neoplasms but are usually easily distinguished from malignancy on routine histopathology. However, in occasional cases the proliferating spindle cells may histopathologically mimic sarcoma, particularly on small biopsies and needle aspirates. Strong intranuclear immunopositivity for p53 protein is presumed to be indirect evidence of mutation of the p53 tumor suppressor gene and can be detected in many malignancies. In order to determine the utility of p53 immunostaining in differentiating IPT occurring in the lung from sarcoma involving the lung, we immunostained eight solitary IPTs, one IPT that recurred repeatedly over a 10-year period, six sarcomas (two malignant fibrous histiocytomas, two metastatic high-grade sarcomas, one metastatic alveolar soft part sarcoma, and one fibrosarcoma) involving the lung, and one IPT from which a sarcoma arose 10 years after radiation therapy. Immunohistochemistry was performed on 5-microns formalin-fixed sections using a commercially available antibody to the p53 protein (Biogenex, monoclonal 1:200) and a standard antigen retrieval technique. Weak intranuclear staining occurring in less than 10% of proliferating cells was not considered a true immunopositive. All eight of the solitary IPTs were immunonegative for p53 protein by our criteria. The IPT that recurred a number of times and the IPT from which a sarcoma later developed were also immunonegative for p53 protein. Four of the six sarcomas were immunopositive, as was the postradiation sarcoma arising from a p53-immunonegative IPT.(ABSTRACT TRUNCATED AT 250 WORDS)