Microscopically, differentiating desmoplastic trichoepithelioma from morpheaform/infiltrative basal cell carcinoma can be difficult as both show 'islands and strands of basaloid cells embedded in a sclerotic stroma'. A superficial shave biopsy further compounds the diagnostic conundrum. Although a plethora of immunohistochemical markers have been touted as being of use as adjunct histologic tools, none thus far appears to be consistent and reliable in terms of specificity and/or sensitivity. Fibroblast-activation protein, a type II membrane-bound glycoprotein belonging to the serine protease family, is expressed in the granulation tissue of healing wounds. More recently, it has been identified as a marker of reactive tumor stromal fibroblasts, as it is reportedly selectively expressed in peritumoral stromal fibroblasts of multiple epithelial cancers including cutaneous malignancies such as basal cell carcinoma. Given this, we sought to ascertain the use of fibroblast-activation protein in distinguishing morpheaform/infiltrative basal cell carcinoma from desmoplastic trichoepithelioma. Immunohistochemical staining for fibroblast-activation protein was performed on desmoplastic trichoepithelioma (n=25) and morpheaform/infiltrative basal cell carcinoma (n=25), with the control group comprising scars from reexcision specimens (n=10). As expected, fibroblast-activation protein expression was observed in stromal fibroblasts of all control cases (10 of 10, 100%). Of interest, fibroblast-activation protein expression was observed in peritumoral fibroblasts of all cases of morpheaform/infiltrative basal cell carcinoma (25 of 25, 100%) but not in any cases of desmoplastic trichoepithelioma (0 of 25, 0%). A gradient of fibroblast-activation protein expression was observed in morpheaform/infiltrative basal cell carcinoma with more intense expression noted in fibroblasts abutting the tumor cells, a less intense expression in the distal peritumoral stromal portion, and minimal to loss of expression in adjacent normal tissue. In summary, findings from this study underscore the use of fibroblast-activation protein as a histologic adjunct in confidently differentiating morpheaform/infiltrative basal cell carcinoma from desmoplastic trichoepithelioma.