CD3O is a member of the tumor necrosis factor (TNF) receptor family, originally described as a marker for Hodgkin and Reed‐Sternberg cells in Hodgkin's disease, which has been found to be preferentially expressed by T cells producing Th2‐type cytokines. The presence of CD3O expression was assessed by both immunohistochemistry and reverse transcriptase‐polymerase chain reaction in the target organs of patients with Th1‐ or Th2‐dominated disorders. CD3O expression was found in neither the gut of patients with Crohn's disease nor in the gastric antrum of Helicobacter pylori‐infected patients, where there was high interferon‐γ (IFN‐γ) expression. In contrast, high CD3O expression in the apparent absence of IFN‐γ expression was observed in the skin of patients with systemic sclerosis or chronic graft versus host disease (GVHD), which can be considered Th2‐dominated disorders. Moreover, high levels of soluble CD3O were found in the serum of both systemic sclerosis and GVHD patients but not in the serum of patients suffering from multiple sclerosis, a Th1‐dominated disorder. Thus, CD3O expression appears to be preferentially associated with Th2‐type responses not only in vitro but also in vivo. J. Leukoc. Biol. 61: 539–544; 1997.