BACKGROUND The clinical significance of scattered or grouped cytoid bodies seen on direct immunofluorescence (DIF) examination has not been systematically analyzed in a variety of disorders. METHODS We prospectively studied skin biopsy specimens obtained from July 2002 to December 2005 for which DIF examination using immunoglobulin (Ig) A, IgG, IgM, C3 and fibrinogen had been performed. Slides with cytoid bodies were further reviewed to assess the number, intensity and location of the cytoid bodies and for other specific findings. These data were compared with both clinical records in the medical charts and pathologic findings from concurrent skin biopsies. RESULTS Of 1080 DIF examinations performed during the study period, 117 (10.8%) had cytoid bodies. These specimens were from patients with 28 different cutaneous disorders, the most common of which were various forms of lupus erythematosus (29/117, 24.8%) and erythema multiforme (22/117, 18.8%). In 81 (69.2%) of these specimens, interface dermatitis was found histopathologically. CONCLUSIONS Cytoid bodies are not infrequent on DIF examination and, in the absence of a clear diagnosis, might point toward several common disorders, particularly those involving interface dermatitis.