Fluoroquinolones are popular antibiotics used for a myriad of conditions including ocular procedures. Despite numerous case reports of acute pigmentary degeneration of the iris with fluoroquinolone use, a pharmacoepidemiological study has not been performed to examine and quantify this risk. Retrospective cohort study with a case-control analysis. A cohort of 1,231,881 new users of oral or topical moxifloxacin, levofloxacin, and azithromycin were followed to first diagnosis of pigmentary degeneration of the iris or pigmentary glaucoma. Four controls were selected for each case using density sampling, matching on age and calendar time. Users of oral or topical moxifloxacin were compared to levofloxacin and azithromycin, a negative control drug from a separate class. First incidence of pigmentary degeneration of the iris or pigmentary glaucoma. The cohort was comprised of 1,231,881 new users of topical or oral levofloxacin, moxifloxacin, or azithromycin. 542 cases of pigmentary degeneration of the iris and 460 cases of pigmentary glaucoma were identified. The incidence of iris pigmentary degeneration or pigmentary glaucoma for topical moxifloxacin was 10.2/1000 person years compared to 2.6/1000 person years for topical azithromycin. Current topical moxifloxacin users had the highest adjusted IRR for pigmentary degeneration of the iris (IRR = 6.81, [95%CI:2.00-23.18]) and pigmentary glaucoma (IRR = 4.07 [95%CI:1.42-11.62]) respectively. The study findings suggest that patients using topical moxifloxacin may have increased risk of developing pigmentary degeneration of the iris and pigmentary glaucoma although the absolute increase was low. Future studies are needed to confirm this association.