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Purpose The number of novel oral anticancer agents is increasing, but financial barriers may limit access. We examined associations between out-of-pocket (OOP) costs and reduced and/or delayed treatment initiation. Methods This retrospective claims-based study used 2014 to 2015 data from a large, proprietary, integrated database and included Medicare and commercial insurance enrollees with a new, adjudicated prescription for any of 38 oral anticancer agents. We examined rates of claim reversal (failure to purchase approved prescription), delayed initiation (reversal with subsequent fill of same agent within 90 days after adjudication), and abandonment (reversal with no fill of same agent within 90 days after adjudication) for the index oral anticancer agent. We also examined whether patients filled any alternate oral, injectable, or infusible anticancer agent within 90 days. Logistic regressions controlled for sociodemographic, clinical, and treatment characteristics to estimate adjusted rates. Results Among the final sample (N = 38,111), risk-adjusted rates of claim reversal ranged from 13% to 67%, increasing with higher OOP costs. Although the abandonment rate was 18% overall, risk-adjusted rates were higher in greater OOP cost categories (10.0% for ≤ $10 group v 13.5% for $50.01 to $100 group, 31.7% for $100.01 to $500 group, 41.0% for $500.01 to $2,000 group, and 49.4% for > $2,000 group; P < .001 compared with ≤ $10 group). Rates remained similar after accounting for use of alternate oral, injectable, or infusible anticancer agents. Delayed initiation was also more frequent for higher OOP cost categories (3% in ≤ $10 group v 18% in > $2,000 group; P < .001). Sensitivity and subgroup analyses by insurance type, pharmacy type, sex, and indication identified similar associations. Conclusion Higher OOP costs were associated with higher rates of oral prescription abandonment and delayed initiation across cancers. Fiscally sustainable strategies are needed to improve patient access to cancer medications.