Interleukin 1 (IL 1) production is stimulated by infection, cellular injury, and inflammation. This cytokine directs a wide spectrum of host responses. Human interleukin 1α (IL 1α) was used to examine the time course of effects on zinc metabolism as part of the acute phase response. IL 1 produced a transient depression in the serum zinc concentration and increased serum ceruloplasmin. Metallothionein levels were increased in liver 14‐fold after IL 1. Increased expression of metallothionein‐1 and ‐2 genes following IL 1 were observed in liver, bone marrow, and thymus. Pulse‐labeling experiments with i.v.‐administered65Zn showed that IL 1 drastically altered zinc distribution kinetics among tissues. More65Zn was taken up (and/or retained) by the liver, bone marrow, and thymus 6 h after IL 1, whereas correspondingly less65Zn was found in bone, skin, and intestine. Uptake by other tissues was not affected by IL 1. Chromatography of cytosol from tissues with increased65Zn uptake suggests the IL 1‐induced redistribution may be driven by enhanced metallothionein synthesis. Collectively, the results show that IL 1 regulates zinc metabolism and may direct its preferential, tissue‐specific distribution via elevated metallothionein‐1 and ‐2 gene expression.—Cousins, R. J.; Leinart, A. S. Tissue‐specific regulation of zinc metabolism and metallothionein genes by interleukin 1.FASEB J.2: 2884‐2890; 1988.