Gene mutation of p53 is documented in head and neck cancer. No reports exist relating human sinonasal inverted papilloma (IP) and its transformation to squamous cell carcinoma (SCC). Using immunohistochemical techniques improved by an antigen retrieval method, p53 protein was analyzed in the following subjects: 16 IP, 12 SCC arising in IP, and 15 SCC alone subjects. Both the intensity (PI) and rate (PR) of positive p53 immunostaining were evaluated using a quantitative AutoCAD program. We correlated p53 protein expression with clinical features. p53 immunoreactivity is significantly lower in IP than in SCC specimens. Both the IP and SCC portions of IP synchronous SCC subjects showed similar p53 protein expression. SCC arising in IP shows a lower p53 immunoreactivity than SCC alone. Alteration of p53 protein may have an important role in the early stages of IP malignant transformation and prove a potential biomarker for risk assessment. Low p53 immunoreactivity, indicating the presence of a wild-type p53, may correlate with the prognosis for SCC arising in IP. However, further clinical trials are required to investigate this possibly worthwhile prognostic marker.