ConA at high concentrations inhibits lymphocyte mitogenesis. Previous studies have shown that inhibitory conA concentrations do not inhibit the acquisition of responsiveness to interleukin-2 (IL-2) when excessive conA is removed. To analyse further the problem of high-dose inhibition by conA, we determined whether inhibition of mitogenesis is related to inhibition of IL-2 production or, alternatively, whether factor production is intact, but the cells are rendered incapable of responding to the factor. ConA stimulates IL2 production at concentrations that are inhibitory to mitogenesis of human lymphocytes. IL-2 was assayed both in a murine cytotoxic T cell line and human memory cells. The response of IL-2-dependent cells to Il-2-containing medium was, on the other hand, inhibited by conA in a dose-dependent fashion. One mechanism whereby high conA concentrations inhibit mitogenesis is by rendering cells resistant to IL-2, possibly via extensive cross-linking of cell surface sites.