SDS-PAGE analysis of plasma samples from mice injected with high, but nontoxic, concentrations of indomethacin led to the detection of elevated levels of a 125,000 dalton protein. The appearance of this protein was rapid, occurring within 24 hrs after a single injection of the drug. Treatment of mice with similar concentrations of sulindac and derivatives, the indomethacin analogs MK-410 and MK-555, or high doses (1 mg/day) of aspirin, did not induce the appearance of this protein. However, the appearance of this protein was rapidly induced by inflammatory agents such as turpentine or bacterial lipopolysaccharide. In addition, the protein was induced by RES stimulating agents such as C. parvum and BCG but it was not induced in tumor-bearing animals with activated RE systems. Administration of [3H]-leucine to animals treated with indomethacin, turpentine or lipopolysaccharide revealed the accelerated synthesis of primarily the 125 kilodalton protein but also the synthesis of several other plasma proteins as well. These results indicate that treatment of mice with indomethacin uniquely induces changes in plasma proteins with the characteristics of an acute phase response. This ability of indomethacin may reside in its ability to activate murine macrophages.