Continuous indomethacin (INDO) administration in the drinking water (10 to 20 μg/mL) profoundly inhibited plasmacytoma (PCT) development initiated by three 0.2- or 0.5-mL intraperitoneal (i.p.) injections of pristane in hypersusceptible BALB/c.DBA/2-Idh1-Pep3 congenic mice. The most effective inhibitions were obtained with continuous INDO treatment. When treatment was delayed until 50 to 60 days after the first pristane injection, there was approximately a 50% reduction in PCT incidence. The primary action of pristane is the induction of a chronic inflammation in the peritoneal connective tissues and the formation of a microenvironment where PCTs develop. INDO, a powerful inhibitor of prostaglandin synthases (cyclooxygenases 1 and 2), did not inhibit the formation of mesenteric oil granuloma nor the appearance of cells in this chronic inflammatory tissue carrying c-myc illegitimately joined to an Ig heavy chain switch region, ie, the t(12; 15) chromosomal translocation. INDO inhibited PCT induction by the i.p. implantation of 21 × 2 mm polycarbonate discs. These solid objects predominantly induce the formation of a patchy fibroplastic tissue on contacting peritoneal surfaces. These and previous data indicate that indomethacin inhibits an intermediate stage in PCT development after the arrival of cells bearing the T(12; 15) translocation in the oil granuloma and before these cells acquire transplantability to a pristane-conditioned host. The biological mechanism that explains how INDO inhibits PCT development is not yet established but appears to result from decreased production of prostaglandins in chronic inflammatory tissues (oil granuloma, fibroplasia), suggesting that prostaglandins play an active role in oil and solid plastic induced PCT formation.