Purpose: To explore the relationship between topical antiglaucoma therapy, both prostaglandin and non-prostaglandin based eyedrops, and persistence of epiphora in glaucoma patients who underwent EN-DCR surgery for PANDO. Methods: prospective observational cohort study of all over 65 years-old patients with a dacryo-CT documented diagnosis of PANDO who underwent EN-DCR, were affected by glaucoma and treated with either topical monotherapy prostaglandin eyedrops or other antiglaucoma molecules, up to 12-month postoperative follow-up. Patients were assessed with Fluorescein Dye Disappearance Test and Munk scale. Results: Fifteen right eyes from 15 PG-group patients and 15 eyes right eyes from 15 non-PG-group patients were considered. Epiphora occurred in 1/15 (7%) of PG-group patients at 3 months, in 8/15 (53%) at 6 months, and in 11/15 (73%) at one year. In comparison, only 1/15 of non-PG-group patients developed epiphora at 6 months. The relative risk of epiphora in PG-group patients versus non-PG-group patients was 3.00 (95% CI, 0.13–68.1; p = 0.99) at 3 months, 8.00 (95% CI, 1.14–56.3; p = 0.014) at 6 months, and 11.0 (95% CI, 1.62–74.9; p < 0.001) at 12 months. Conclusion: Based on our results, we speculate that prostaglandin eye drops may affect the outcome of EN-DCR in terms of increasing epiphora recurrence from early to late postoperative follow up. The toxicity of antiglaucoma eye drops might damage spiral fibers of the mucous membrane of the lacrimal system inducing fibrosis by a proinflammatory mechanism.