Peripheral blood mononuclear cells (PBMC) from patients with systemic sclerosis (SSc) produced increased amounts of interleukin-2 (IL-2), in a dosedependent manner, in response to stimulation with human type I collagen, whereas PBMC from normal subjects did not. At a dose of 50 p g human type I collagen/106 PBMC, PBMC from SSc patients (n = 17) produced 8 times as much IL-2 as did PBMC from 16 normal subjects (P < 0.005) and 3 times as much as did PBMC from a group of 13 rheumatoid arthritis patients (P < 0.05). In contrast, IL-2 production by PBMC after nonspecific stimulation with the mitogen, phytohemagglutinin, did not differ among the SSc, rheumatoid arthritis, and normal control groups. Cell depletion experiments indicated that the IL-%producing cells in SSc patients are CD4+. Thus, SSc patients have CD4 cells that are specifically sensitized to human type I collagen and can produce increased levels of IL-2.