OBJECTIVES We identify commonly-reported reasons that patients with chronic disease either do not fill a new medication prescription (non-fulfillment) and/or elect to stop taking a medication without their physician telling them to do so (non-persistence). METHODS Participants were sampled from a nationally-representative, internet-based panel of US adults with chronic diseases. 29,018 eligible respondents answered questions about medication fulfillment or persistence and their medication-related beliefs. We collected reasons for non-fulfillment or non-persistence. Statistical analyses were conducted to assess the association between reported reasons and chronic disease, demographics, or beliefs. RESULTS Among the 11,301 respondents who had received at least one new prescription in the previous year, 3.8% reported never filling the prescription. Non-fulfillment rates ranged from 1.9% for diabetes to 11.0% for osteoporosis. Among the 28,973 respondents currently prescribed medication(s), 13.7% reported non-persistence for at least one prescription in the previous year. Non-persistence was highest for medications for osteoporosis (19.1%), and lowest for respondents with hypertension medications (5.6%). Three reasons were the most commonly reported for non-fulfillment and non-persistence: cost-related barriers (51% and 42%, respectively), medication concerns (47% and 50%), and low perceived need for medications (30% and 31%). The frequency of the reasons for non-persistence varied substantially by chronic disease (all P≤0.02). CONCLUSIONS Future efforts to improve medication adherence should address patients' medication concerns, perceived need for medications, and perceived medication affordability. The results of our study can inform the design and evaluation of adherence interventions.