To assess the use of anti-CD34 and anti-factor-XIII a antibodies for the differential diagnosis of dermatofibroma (DF) and dermatofibrosarcoma protuberans (DFSP), we stained 40 DFs and 13 DFSPs. A significant population of dendritic and spindle cells was reactive with anti-factor-XIII a in 90% of DFs. In DFSP, most cases had very few or no reactive cells for this antiserum and reactivity was confined to the infiltrating edges of the neoplasm or to a very low percentage of cells within the bulk of the tumor. A significant overlap was detected, a reason why the stain is useful but lacks absolute specificity for this purpose. Human progenitor cell antigen (CD34) was found in all cases of DFSP that had 50–100% of reactive e cells, but in only five DFs. In DFs, the reactivity for CD34 was focal, with only ≤20% positive cells. When used together with other histopathological criteria, factor-XIIIa antibody and particularly CD34 may help to differentiate these two processes.