Probucol, 4,4'‐(isopropylidenedithio)bis(2,6‐di‐tert‐butylphenol), has been shown to inhibit atherogenesis in genetically hypercholesterolemic (Watanabe) rabbits. Since atherosclerotic lesions contain macrophages capable of screting interleukin 1 (IL 1) and other cytokines that could contribute to the pathogenesis of the disease, we have investigated whether probucol affects IL 1 secretion. Resident peritoneal macrophages from mice dosed with probucol secreted 40‐80% less IL 1 than macrophages from control animals when stimulated in vitro with lipopolysaccharide (LPS). The inhibitory effect of probucol was observed when IL 1 was assayed by the standard bioassay, the thymocyte proliferation assay, or a competitive IL 1 receptor binding assay. Probucol treatment had no effect on LPS‐induced membrane IL 1 expression; secretion of tumor necrosis factor (TNF); Con A‐induced splenic interleukin 2 (IL 2) and interleukin 3 (IL 3) release; and prostaglandin‐ or zymosan‐induced secretion of prostacyclin, leukotriene C₄, acid phosphatase, or superoxide anion. In contrast to the effect of oral administration, direct addition of probucol to macrophage cultures did not inhibit IL 1 release. Probucol administration did, however, inhibit the fall in serum zinc level induced by intravenous injection of LPS in zymosan‐primed mice but had no effect on the LPS‐induced increase in serum triglyceride levels, which indirectly confirms that probucol administration inhibits IL 1 but not TNF secretion. Paw granuloma induced in mice by heat‐killed mycobacteria was inhibited by oral administration of probucol, an effect that may be attributable to inhibition of IL 1 secretion. Probucol neither reduced zymosan‐induced liver granulomata in mice nor inhibited adjuvant‐induced arthritis in rats. We suggest that inhibition of IL 1 secretion from macrophages by probucol contributes to its therapeutic effects in atherosclerosis and may also result in beneficial activity in some chronic inflammatory diseases.— Ku, G.; Doherty, N. S.; Schmidt, L. F.; Jackson, R. L.; Dinerstein, R. J. Ex vivo lipopolysaccharide‐induced interleukin 1 secretion from murine peritoneal macrophages inhibited by probucol, a hypocholesterolemic agent with antioxidant properties. FASEB J. 4: 1645‐1653; 1990.