Cultured T cells and freshly isolated mononuclear leukocytes are able to bind collagen specifically. These leukocytes express equivalent levels of the integrins VLA-1, VLA-2 and VLA-3 which are collagen-binding receptors on other cells. However, only solubilized VLA-2 is able to bind collagen and only monoclonal antibodies specific for alpha 2 or beta 1 subunits are able to block the binding of intact cells to collagen. This restriction provides another example of the dependence of integrin specificity on the cell type on which it is expressed. It was also speculated that the inserted or I domain on the alpha subunits of VLA-1, VLA-2 and the beta 2 integrin family might have a role in collagen binding on the basis of its sequence homology to other types of collagen binding proteins. However, LFA-1, CR3 and p150,95 showed no collagen binding activity, suggesting that the I domain has another function.