Atypical fibroxanthoma (AFX), a pleomorphic superficial cutaneous tumor of low-grade malignancy, shares many morphologic features with malignant melanoma (MM) and squamous cell carcinoma (SCC). Absence of S-100, keratin, and desmin immunoreactivity is the clue for this diagnosis. In a search for positive markers, we tested 26 cases of AFX with 2 antibodies: O13 (CD99) and protein gene product 9.5 (PGP9.5). We also included 10 cases of poorly differentiated SCC and 10 cases of MM in the study. In AFX, CD99 immunoreactivity was present in 19 cases (73%), whereas focal PGP9.5 immunoreactivity was found in only 9 cases (35%). None of the SCC cases showed CD99 immunostaining. No CD99 immunoreactivity was found in 9 of 10 cases of MM. To our knowledge, this is the first report of CD99 and PGP9.5 immunostaining in AFX. We believe, based on our results, that CD99 may be a helpful "positive" feature in the histopathologic diagnosis of AFX.