A study of the clinical, histological, and immunohistochemical features of 20 cases of deep penetrating dermatofibroma (DPDF) and eight cases with 14 specimens (eight primary, one reexcision, five secondary tumors) of dermatofibrosarcoma protuberans (DFSP) showed distinct entities. Clinically, DPDF usually appeared as a nodule (-2 cm) of the (lower) limbs, whereas DFSP affected the trunk (shoulder) with irregularly arranged plaques or nodules (>5 cm). Histologically, DFDF showed a regular silhouette with a smooth, nodular (four of 20) or scalloped (16 of 20) lower margin and variable sclerosis (nine of 20): DFSP, irregularly infiltrated fatty tissue in a lacelike/honeycomb (eight of 14), multilayered (three of 14), or mixed pattern (three of 14), but without sclerosis. Immunohistochemically, DPDF was mostly negative with QBEnd 10(CD34; 18 of 20) but positive for factor XIIIa (17 of 20), actin (HHF35; 10 of 20), and metallothionein (MT:12 of 20), DFSP was positive for CD34 (13 of 14), yet with some sparing of central tumor parts, highly cellular tumor nodules, and myxoid areas; factor XIIIa and MT were consistently negative, as was HHF35 in (1 of 14 caes. In a multivariate analysis of histologic and immunohistochemical criteria, the combination of sclerosis and labeling with MT was most valid (p= 0.0001) for diagnosis: all DPDF showed either labeling with MT in “early” (metabolically active) lesions or sclerosis in “late” lesions, not present in DFSP.