Previous studies of mast-cell density and histamine content in biopsy specimens in patients with Crohn's disease have yielded conflicting results. In this in vivo study we have measured the jejunal secretion rate of histamine in patients with Crohn's disease (n = 15) of the terminal small bowel and in healthy controls (n = 24). The secretion studies were performed using a recently developed segmental jejunal perfusion system with a two-balloon, six-channel small tube. The histamine secretion rate was 152 +/- 29 (SEM) ng/cm small intestine per h in patients with Crohn's disease, which meant a significant increase (p less than 0.01) compared with the secretion rate in controls (71 +/- 11 ng/cm per h). Moreover, the secretion of histamine was related to the disease activity. Patients with active disease (n = 8) (i.e., Crohn's disease activity index greater than 150) had a mean histamine secretion rate of 193 +/- 47 ng/cm per h, while patients with inactive disease (Crohn's disease activity index less than 150) had a secretion rate not significantly increased compared with controls (105 +/- 24 ng/cm per h). The present data indicate increased mast-cell involvement of the small intestine in active Crohn's disease of the distal ileum. This finding might reflect the systemic nature of the disease process.