Medication nonadherence is a major obstacle to better control of glucose, blood pressure (BP), and low-density lipoprotein cholesterol (LDL) in adults with diabetes. Inexpensive, effective strategies to increase medication adherence are needed. We randomly assigned 2.378 adults with diabetes mellitus who were recently prescribed a new medication for elevated glycated hemoglobin (A1c) >= 8%, BP >= 140/90 mm Hg, or LDL >100 mg/dL, to receive (a) one scripted telephone call from a diabetes educator or clinical pharmacist to identify and address nonadherence to the new medication or (b) usual care. Hierarchical linear and logistic regression models were used to assess impact on (a) first medication fill within 60 days of prescription, (b) >=2 medication fills within 180 days of prescription, and (c) clinically significant improvement in A1c, BP, or LDL. Of the 2,378 subjects, 89.3% in the intervention and 87.4% in usual care group had sufficient data to analyze study outcomes. In intent-to-treat analyses, the intervention was not associated with significant improvement in primary adherence, medication persistence, or intermediate outcomes of care. Results were similar across subgroups of patients defined by age, sex, race/ethnicity, and study site and when limiting analysis to those who completed the intended intervention. This inexpensive and well-received intervention did not significantly improve medication adherence or control of glucose, BP, or lipids. Wide use of this strategy does not appear to be warranted; alternative approaches to identify and improve medication adherence and persistence are needed.