In a randomized clinical trial, the authors compared the use of postoperative subconjunctival injections of 5-fluorouracil (5-FU) in 19 eyes with a single intraoperative application of subconjunctival mitomycin (MMC) at the filtering site in 20 eyes at high risk for failure of glaucoma filtering surgery. Six months after surgery, intraocular pressures averaged 10.9 +/- 5.3 mmHg (mean +/- standard deviation) in the MMC-treated eyes versus 14.2 +/- 5.5 mmHg in the 5-FU-treated eyes (P = 0.08) and were less than or equal to 12 mmHg in 60.0% of MMC-treated eyes and 21.1% of 5-FU-treated eyes (P = 0.03). Mitomycin-treated eyes were receiving an average of 0.3 +/- 0.5 medications for intraocular pressure control, and 5-FU-treated eyes were receiving an average of 1.1 +/- 1.1 medications (P = 0.01). Drug-induced corneal epithelial defects were seen in nine 5-FU-treated eyes and in no MMC-treated eyes (P = 0.0004). These results suggest that intraoperative MMC may be a viable alternative to postoperative 5-FU, with lower overall intraocular pressures, decreased dependence on postoperative ocular antihypertensive medications, and decreased corneal toxicity.