Thirty-three patients with atopic dermatitis underwent double-blind placebo-controlled food challenges for evaluation of the role of histamine in hypersensitivity to food. After suspect foods were eliminated for 10 days, oral challenges were performed with up to 8 g of dehydrated food. A total of 35 positive challenges elicited symptoms that were cutaneous (31), gastrointestinal (17), nasal (8), and respiratory (6) within 10 to 90 minutes. Forty-one food challenges were negative, and all 60 placebo challenges were negative. Only the group of patients with positive food challenges had a significant mean (+/- S.E.M.) rise in the plasma histamine concentration, from 296 +/- 80 pg per milliliter before challenge to 1055 +/- 356 after challenge (P less than 0.001). Rises in plasma histamine that were seen after these positive oral food challenges implicate mast-cell or basophil mediators in the pathogenesis of food allergy, including cutaneous changes in patients with atopic dermatitis.