MOST patients with non-insulin-dependent diabetes mellitus are resistant to both endogenous and exogenous insulin(1). Insulin resistance precedes the onset of this disease(2-4), suggesting that it may be an initial abnormality. Insulin-receptor kinase activity is impaired in muscle, fibroblasts and other tissues of many patients with non-insulin-dependent diabetes mellitus(5), but abnormalities in the insulin-receptor gene do not appear to be the cause of this decreased kinase activity(6,7). Skin fibroblasts from certain insulin-resistant patients contain an inhibitor of insulin-receptor tyrosine kinase(8,9). Here we show that this inhibitor is a membrane glycoprotein, termed PC-1 (refs 10,11). We find that PC-1 activity is increased in fibroblasts from seven of nine patients with typical non-insulin-dependent diabetes mellitus. In addition, overexpression of PC-1 in transfected cultured cells reduces insulin-stimulated tyrosine kinase activity. These studies raise the possibility that PC-1 has a role in the insulin resistance of non-insulin-dependent diabetes mellitus.