We investigated the effect of a pH 4-treated human immunoglobulin preparation for intravenous use (pH4-G) on the production of tumor necrosis factor alpha (TNF-alpha) in vivo. The level of TNF-alpha in the sera of rabbits receiving pH4-G before lipopolysaccharide (LPS) injection was lower than that in rabbits receiving only LPS. Similarly, the in vitro production of TNF-alpha was suppressed by pH4-G. Rabbit peritoneal exudate cells stimulated with LPS in the presence of pH4-G produced less TNF-alpha than did those stimulated only with LPS. pH4-G, however, had no effect on various TNF-alpha activities, such as cytotoxicity against tumorigenic murine fibroblasts (L929 cells), induction of interleukin-1 production, or fever induction. These results indicate that pH4-G suppresses TNF-alpha production without affecting TNF-alpha activities. A suppressive effect on the expression of TNF-alpha mRNA was also observed.