PURPOSE:: To examine the efficacy and clinical characteristics of successful full-thickness macular hole closure with topical therapy. METHODS:: Retrospective case series of full-thickness macular holes managed by a single retinal physician (DS) diagnosed and treated from 2017 to 22. RESULTS:: Of 168 patients with full-thickness macular holes, 71 patients were started on steroid, carbonic anhydrase inhibitor, and nonsteroidal antiinflammatory (NSAID) drops. 49 patients (mean 67 years, 59% women) were included in the analysis, and 22 patients were excluded for poor follow-up. In total, 7/49 were secondary post-PPV holes and 42/49 were idiopathic. In addition, 18/49 eyes (36.7%) achieved closure on topical therapy, of which 13 were idiopathic. Hole size was directly correlated with odds of closure: for every 10 μm decrease in size and odds of closure increased by 1.2× (P = 0.001, CI 1.1–1.4). Average time to closure was 107.2 days (range 20–512 days) and was not correlated with hole size (P = 0.217, CI −0.478 to +1.938). The presence of VMT was found to be inversely related to successful closure (OR 6.1, P = 0.029, CI 1.2–31.3). There was no significant difference in final best-corrected visual acuity for eyes undergoing primary pars plana vitrectomy versus those trialing drops before undergoing pars plana vitrectomy (P = 0.318, CI −0.094 to +0.112). CONCLUSION:: In the first study to date to report the overall efficacy and clinical characteristics of successful macular hole closure with topical therapy, drops achieved an overall closure rate of 36.7%, with higher efficacy in smaller holes and those without VMT. Rates of MH narrowing and reduction in central foveal thickness acted as predictors of effectiveness of drop therapy.