OBJECTIVES: With increasing use and cost of oral oncology medications, patient non-adherence with oral therapy is of greater concern.  This study sought to evaluate the magnitude and predictors of non-adherence among patients receiving oral therapy for HCC accounting for patient-level variation in total duration of treatment and dose-changes. METHODS: This retrospective cohort study used an employer-based, commercially available, large claims database (2005-2011) to identify adult patients with ≥ 2 diagnoses of HCC (ICD-9 155), and ≥ 2 filled prescriptions for sorafenib - the only approved oral therapy for HCC.  Additional study inclusion criteria were not having other previous cancers, and a 3-month wash-out period of no systemic therapy prior to the incident sorafenib fill (index) date.  Adherence was assessed using a modified Proportion of Days Covered (PDC) measure over a patient-specific period from index date to treatment discontinuation.  Non-adherence was categorized as PDC < 85% (base case), with two-way sensitivity analyses using an 80% cut-off and allowance for gaps due to dose change/Adverse Events.  Logistic models were estimated to identify predictors of non-adherence. RESULTS: A total of 1,100 patients (median age = 61 years; 78% male) met eligibility criteria.   Median sorafenib 30-day co-pay was $25 (5% > $500).   25% of patients had prior procedures.  Median total sorafenib exposure was 120 days (Q1=68; Q3=223).  14.5% and 13.5% patients had down/up-titrated fills from median index dose of 800 mg/day and 400 mg/day respectively.  Median PDC was 98%; 15% of patients were non-adherent.  Younger (below-median) age (OR=1.5; p=0.02) and prior procedures (OR=1.7; p=0.003) were robust predictors of non-adherence. CONCLUSIONS: Using a modified PDC approach to account for varying and relatively short durations of treatment until progression/death in HCC, over 15% of patients were found non-adherent.  Evidence on the predictors of non-adherence should be confirmed in the context of other, newly emerging oral therapies and may guide patient education and other compliance-enhancing initiatives.