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The histopathology of cutaneous lesions of dermatomyositis (DM) may be indistinguishable from acute cutaneous lesions of systemic lupus erythematosus (SLE). Misreported or incomplete clinical information may result in a clinicopathologic discrepancy and a delay in making a correct diagnosis of DM. The aim of this study was to systematically characterize the histopathologic findings of cutaneous lesions of DM and to determine if skin biopsy specimens of DM and SLE could be distinguished by light microscopic examination. Biopsies from 40 patients diagnosed with DM at the Wake Forest University School of Medicine from 1994 to 1999 were reviewed. The histological features by light microscopy were graded in a systematic fashion. We then assessed whether the cutaneous pathological changes of DM could be distinguished from those of SLE. Ten biopsy specimens each of DM and SLE (matched for anatomical site and lesion morphology) were randomized. Histological grading was performed in a blinded fashion, as was a histopathologic diagnosis (DM versus SLE). The most consistent histological findings of DM included increased dermal mucin, vacuolar alteration of the basal cell layer, and mild-to-moderate mononuclear cell inflammatory infiltrates. Our results show that the histological grading of SLE skin biopsies was nearly identical to that of DM. The correct histopathologic diagnosis of DM or SLE was made in 11 of the 20 skin biopsies without clinical information. Despite the limitations of our small sample size, these findings suggest that acute cutaneous lesions of SLE cannot be distinguished from DM. Clinicopathologic correlation is important for making a diagnosis of DM or SLE.