Objective: To compare the effectiveness of trabeculectomy with adjunctive, low-dose, subconjunctival 5-fluorouracil (5-FU) to trabeculectomy alone in patients with uncomplicated glaucoma undergoing their first incisional surgical procedure. Design: Retrospective, nonrandomized comparative trial. Participants: Consecutive series of 52 patients and 74 control subjects. Interrelation: Trabeculectomy was performed in all patients. Study patients received adjunctive, subconjunctival injections of 5-FU up to 14 days from the date of surgery. Main Outcome Measures: Intraocular pressure, number of postoperative antiglaucoma medications, interventions, and complications were evaluated. Results: Mean followup for all patients was 58.1 ± 44.1 months (range, 1.1-159.9 months). Mean followup for successful eyes was 55.9 ± 47.1 months (range, 7.6-159.9 months). The cumulative 5-year success (intraocular pressure [IOP] ≤ 21 mmHg) was 77.8% in the 5-FU group and 62.2% in the control group (P = 0.02, Wilcoxon test. Complete success (IOP ≤ 21 mmHg without medications) at 5 years was lower in both the 5-FU group (72.3%) and the control group (51.3%). Postoperative mean IOP at 5 years for all successful patients was lower in eyes receiving 5-FU (10.7 ± 3.6 mmHg vs. 16.0 ± 6.1 mmHg [P = 0.02, t-test]). For those patients considered to be complete successes, there was no difference in IOP between the two groups of patients at any evaluated time interval. Patients in the 5-FU group were using 0.7 ± 1.1 medications at final followup compared with 1.8 ± 1.4 medications in the control group (P = < 0.0001, t test). Bleb-related ocular infection occurred in 6.3% of patients and was more common in patients receiving 5-FU than controls (6 of 52 vs 2 of 74, respectively; P = 0.05, Fischer's exact test). Conclusions: Adjunctive, low-dose 5-FU at the time of initial surgery in uncomplicated glaucoma improves long-term IOP control and reduces the need for postoperative, antiglaucoma therapy. Eyes receiving 5-FU are at greater risk of developing late bleb-related ocular infection. (C) 2000 by the American Academy of Ophthalmology.