Studies were undertaken to determine the incidence and nature of serum chemotaxis inhibitors in patients with Crohn's disease and ulcerative colitis. Sera from patients with active Crohn's disease were shown to contain chemotactic factor-directed inhibitory activity. The molecular size of the inhibitor estimated by gel filtration is similar to the 7S gamma-globulins and it is precipitable by 40% ammonium sulfate. Less marked inhibitory activity is present in the same fractions of sera from patients with ulcerative colitis and from healthy controls, suggesting that it represents increased activity of one or more normal serum globulins. Leukocyte-directed serum inhibitors have also been demonstrated in patients with Crohn's disease and ulcerative colitis, particularly in patients with active disease. In Crohn's disease the presence of serum chemotactic factor inhibitors may explain the diminished chemotaxis of neutrophils into skin window chambers reported previously. The inhibitors are nonspecific and are probably secondary to the disease state but may have some bearing on the nature of the mucosal inflammation.