Background: Adherence to long-term pharmacotherapy is problematic in the United States. Bubble packaging of medications has been touted to improve patients’ use of medications. Scant research has assessed bubble packaging’s impact on adherence to multiple medications. Objective: To compare medication adherence between patients receiving medications to address cardiovascular disease risk factors in bubble packages to those receiving medications in pill bottles. Methods: This retrospective cohort study utilized prescription dispensing records from an independent pharmacy. Patients receiving statins, β-blockers, angiotensin-converting enzyme inhibitors, or oral hypoglycemic agents were identified and grouped into those who received medications in bubble packages and those received medications in pill bottles. Adherence was assessed with medication possession ratios. Patients were classified as adherent if their medication possession ratio was 80% or more. Results: Receiving medications in bubble packaging was significantly associated with greater adherence compared to pill bottles (P < .001). In adjusted models, greater numbers of medications filled (P = .024) and increasing patient age (P = .018) were significantly associated with low adherence, while bubble packaging was not (P = .13). Stratified analyses revealed that bubble packaging was significantly associated with greater adherence when 4 or fewer medications are filled (P = .012) and for patients between 18 and 44 years of age (P = .023). Conclusion: Bubble packages can improve medication adherence. However, they may not resolve complex issues contributing to the problem of nonadherence, especially for older patients and those prescribed multiple medications.