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PURPOSE To confirm the prophylactic effect of oral acetazolamide against increased intraocular pressure (IOP) in the period immediately after cataract surgery in eyes with primary open-angle glaucoma (POAG) and to evaluate the appropriate administration time of oral acetazolamide to prevent IOP elevation. DESIGN Randomized clinical study. PARTICIPANTS Ninety eyes of 90 patients with well-controlled POAG scheduled for phacoemulsification. METHODS Eyes were assigned randomly to 1 of 3 groups: (1) oral acetazolamide (500 mg) administration 1 hour preoperatively, (2) oral acetazolamide (500 mg) administration 3 hours postoperatively, or (3) no acetazolamide administration. Intraocular pressure was measured using a rebound tonometer 1 hour preoperatively, at the conclusion of surgery (adjusted in the range between 15 and 25 mmHg), and 1, 3, 5, 7, and 24 hours postoperatively. The incidence of eyes with IOP elevation more than 100% above the preoperative IOP was compared. MAIN OUTCOME MEASURES Postoperative IOP and incidence of eyes with marked IOP elevation. RESULTS Mean IOP 1 hour preoperatively and that at the conclusion of surgery did not differ significantly among groups. In all groups, mean IOP was significantly elevated from 3 to 7 hours postoperatively, and then decreased at 24 hours. At 1 and 3 hours postoperatively, mean IOP was significantly lower in the group receiving oral acetazolamide preoperatively than in the other 2 groups (postoperative administration or no administration; P ≤ 0.0031). At 5, 7, and 24 hours postoperatively, the IOP was significantly lower in both the preoperative and postoperative administration groups than in the nonadministration group (P ≤ 0.0224). Intraocular pressure elevation of more than 100% occurred in 1 eye (3.3%) in the preoperative administration group, 7 eyes (23.3%) in the postoperative administration group, and 8 eyes (26.6%) in the nonadministration group; the incidence was significantly lower in the preoperative administration group (P = 0.0459). CONCLUSIONS Eyes with POAG experienced short-term IOP elevation from 3 to 7 hours after phacoemulsification. Oral acetazolamide administration 1 hour preoperatively significantly reduced the IOP elevation from 1 to 24 hours, while administration 3 hours postoperatively reduced the IOP elevation at 5 hours or more after surgery.