In a prospective, randomized, double-masked study, 2% epinephrine applied topically twice each day for two weeks to the eyes of patients with glaucoma or ocular hypertension caused an 8.1 +/- 1.4-mm Hg (mean +/- S.E.M.) reduction of intraocular pressure in placebo-treated patients, but only a 1.9 +/- 0.6-mm Hg decrease in patients treated with 25 mg of orally administered indomethacin four times each day (P less than .0005). Systemic treatment with indomethacin for one week did not significantly increase intraocular pressure by itself (baseline, 19.7 +/- 0.6 mm Hg, vs 20.1 +/- 1.4 mm Hg after indomethacin treatment). When indomethacin treatment was discontinued in those patients receiving topical epinephrine, there was a further significant (P less than .05) reduction in intraocular pressure compared with the placebo-treated group. Since the ocular hypotensive effect of topically applied epinephrine is inhibited by indomethacin, a cyclo-oxygenase inhibitor, these results suggest that this reduction of intraocular pressure is at least partially mediated by the endogenous production of prostaglandins, or other cyclo-oxygenase products, and that the intraocular pressure of glaucoma patients undergoing epinephrine therapy may increase when systemic cyclo-oxygenase inhibitors such as indomethacin or aspirin are taken.