The role of complement and the mechanism of sulfone action in dermatitis herpetiformis (DH) have not yet been established; prior studies have presented conflicting data regarding the effect of sulfones on complement activation and deposition. Thirty-eight DH patients were studied. Twenty-four of 25 perilesional skin biopsies and 50 of 67 normal-appearing skin biopsies showed the third component of complement (C3) deposited in areas corresponding to those of IgA deposition. Nine of 10 patients with bound C3 in normal-appearing and perilesional skin during periods of active disease continued to have C3 in normal-appearing skin when treatment with sulfones kept them completely free of lesions for 2 to 8 weeks. When either Hartley-strain or C4-deficient guinea pigs were given up to 150 mg/kg sulfoxone (a water-soluble sulfone) intraperitoneally for 8 days before elicitation of active Arthus, reverse passive Arthrus reactions, or Forssman shock, there was no difference in time course, character, or intensity of reactions when compared to saline-treated control animals. We were therefore unable to demonstrate any effect of sulfones on complement deposition in DH skin or on complement activation in classical or alternate complement pathway-mediated guinea-pig reactions.