Endotoxin apparently induces interferon in only a few types of cell, yet it produces strong hyporesponsiveness to a large number of agents. After incubation for 24 hr with endotoxin in vitro, tissue cultures of thymus, spleen, mesenteric lymph nodes, and, to a lesser extent, liver and lung produced interferon. Lymphoid tissues of bone marrow-derived (B-) cells (sacculus rotundus, appendix, and Peyer's patches) and kidney did not produce interferon. Adherent spleen cells produced more interferon than nonadherent cells. Purification of spleen cells on a bovine serum albumin gradient showed that light, DNA-synthesizing cells made interferon in response to endotoxin or polyriboinosinic-polyribocytidylic acid. Mouse spleen cells produced a “late” interferon 24–48 hr after exposure to endotoxin, which, in contrast to “early” interferon (produced at 0–24 hr) from spleen and other tissues, is stable at 56 C for 60 min. It is suggested that this late interferon represents a “B-cell” interferon. Hyporeactivity was produced in vitro by endotoxin only in tissues that make endotoxin-induced interferon, a fact consistent with the theory that the interferon-inducing mechanism must be initiated before hyporeactivity results. The fact that endotoxin has been found to act on a fairly large range of cells (i.e., macrophages, thymus-derived cells, and probably Bvlymphocytes) explains its ability to produce broad hyporesponsiveness.