The effect on intraocular pressure (IOP) of adding prostaglandin F2 alpha-1-isopropyl ester (PGF2 alpha-IE) to timolol was studied in 21 eyes of 13 patients with newly diagnosed primary open-angle glaucoma that was inadequately controlled with timolol alone. After at least 2 weeks of twice daily timolol 0.5% therapy, PGF2 alpha-IE, 0.5 microgram in 30 microliters, was topically applied twice daily at 8 AM and 8 PM, 5 minutes before each timolol dose, for 7 days. Intraocular pressures were measured before timolol treatment, and at 8 AM, 8:30 AM, 12 PM, 2 PM, and 4 PM on the day before the addition of PGF2 alpha-IE, and on day 1 and on day 7 of combined therapy. Mean IOP was 39 +/- 2 mmHg (+/- standard error) before timolol therapy and 31 +/- 2 mmHg after at least 2 weeks of treatment with timolol alone. A significant (P = 0.004) further reduction of IOP was first observed 4 hours after the first dose of PGF2 alpha-IE, which was maintained throughout the duration of combined therapy. During the last day of combined treatment and at 12 hours after the final dose, IOP was reduced a mean of 6 to 9 mmHg (mean, 9.0 +/- 1.5 mmHg at 12 hours) below baseline values obtained with timolol alone. These results indicate that adding PGF2 alpha-IE in patients treated with timolol causes a further reduction of IOP that may prove to be clinically useful in glaucoma therapy.