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Significance: Determining risk factors for posterior capsule opacification will allow for further interventions to reduce the risk of development and thus additional procedures., Purpose: The purpose of this study was to investigate risk factors associated with development of clinically significant posterior capsule opacification requiring yttrium aluminum garnet (YAG) capsulotomy., Methods: Medical records of patients (≥18 years) who underwent cataract surgery between January 1, 2011, and March 31, 2014, at Kresge Eye Institute were reviewed. Three hundred eyes requiring YAG capsulotomy up to 3 years after cataract surgery were included in the YAG capsulotomy group. Three hundred eyes not requiring YAG capsulotomy up to 3 years after cataract surgery were selected via age-matched simple randomization (control group)., Results: The YAG capsulotomy group included patients with younger age (65.8 ± 11.3 vs. 70.1 ± 10.6 years, P < .001), more men (42.67 vs. 34.67%, P = .04), fewer patients with hypertension (73.00 vs. 83.00%, P < .001), and more patients with hydrophilic intraocular lenses (74.67 vs. 47.00%, P < .001). Logistic regression analysis demonstrated a negative association between YAG capsulotomy and age (coefficient, -0.04; 95% confidence interval [CI], 0.95 to 0.98; P < .001) and hydrophobic intraocular lenses (coefficient, -1.50; 95% CI, 0.15 to 0.33; P < .001), and a positive association with presence of glaucoma (coefficient, 0.88; 95% CI, 1.39 to 4.17; P = .002). Elapsed time to YAG capsulotomy was sooner in patients with a history of uveitis (95% CI, 5.10 to 9.70 months; P = .02) and insertion of hydrophilic intraocular lenses (95% CI, 18.67 to 21.57 months; P < .001)., Conclusions: Results of this study suggest that development of visually significant posterior capsule opacification is associated with younger age, glaucoma, and hydrophilic intraocular lenses, and it occurs earlier among those with hydrophilic intraocular lenses and a history of uveitis.