Acute infections are accompanied by tissue insulin resistance, as manifested by worsening of metabolic control in diabetic patients and decreased glucose tolerance in non-diabetic subjects. To clarify the potential role of altered insulin receptor status in this phenomenon, we studied [125I]insulin binding to monocytes in 7 otherwise healthy subjects during acute bacterial and viral infections of moderate severity. The values were compared to those obtained after convalescence (five patients) and those of 24 normal subjects. Insulin binding during infection, at a time when insulin resistance was demonstrable, was indistinguishable from convalescent or normal values. Plasma glucose and insulin levels, the insulin to glucose ratio, as well as plasma GH, cortisol, and FFA were significantly elevated during infection, while plasma glucagon, epinephrine, and norepinephrine levels were normal. We conclude that insofar as monocyte receptors are representative of other tissues, insulin resistance in infection is mediated at the postreceptor level.