Importance Exfoliation syndrome, an inherited systemic disorder of elastin and extracellular matrix (ECM), is associated with the LOXL1 gene locus. Pelvic organ prolapse is a common connective tissue disorder that affects women. The presence of an association between exfoliation syndrome (exfoliation of the lens capsule) and pelvic organ prolapse was investigated as part of the Utah Project on Exfoliation Syndrome (UPEXS). Objective To examine the association between exfoliation syndrome and pelvic organ prolapse using the Utah Population Database, a comprehensive resource linked to medical records. Design, Setting, and Participants A 2-pronged approach was used. In substudy A, a cross-sectional analysis was performed to determine the association between pelvic organ prolapse and exfoliation syndrome in women enrolled in Medicare in Utah from calendar year 1992 to 2009 (n = 132 772). In substudy B, the risk of incident exfoliation syndrome from January 1, 1995, to December 31, 2014, was estimated in a cohort of women aged 30 to 65 years at baseline with a diagnosis of pelvic organ prolapse (n = 5130) compared with birth year-matched women serving as controls who did not have pelvic organ prolapse (n = 15 338). Main Outcomes and Measures Exfoliation syndrome outcome was defined by International Classification of Diseases, Ninth Revision, diagnosis codes for exfoliation syndrome or exfoliation glaucoma (366.11 or 365.52, respectively). In substudy A, odds ratios (ORs) from unconditional logistic regression models were used to estimate the exfoliation syndrome risk in women with pelvic organ prolapse compared with those without pelvic organ prolapse. In substudy B, hazard ratios (HRs) from Cox proportional hazards models were used to estimate incident exfoliation syndrome risk in patients with pelvic organ prolapse (without exfoliation syndrome history) compared with unaffected controls. Models were adjusted for age, years enrolled, parity, and race/ethnicity. Results Of the 132 772 women enrolled in Utah Medicare from 1992 to 2009, the mean [SD] age at the last enrollment was 82.2 [7.7] years. Pelvic organ prolapse was associated with a 1.56-fold increased risk of exfoliation syndrome in Medicare beneficiaries (OR, 1.56; 95% CI, 1.42-1.72) in substudy A. We observed a 48% increased incident risk of exfoliation syndrome in women aged 30 to 65 years at baseline who had a pelvic organ prolapse diagnosis compared with controls during 20 years of follow-up (HR, 1.48; 95% CI, 1.14-1.91). Conclusions and Relevance The diagnosis of exfoliation syndrome was more frequent in women with pelvic organ prolapse in the Utah Population Database, a robust population-based resource, thus supporting an association of exfoliation syndrome with a nonocular systemic condition. Systemic conditions with altered ECM metabolism, such as pelvic organ prolapse, may share common biological pathways with exfoliation syndrome. LOXL1 dysregulation, thought to occur in exfoliation syndrome, may be a contributing factor.