BACKGROUND: The need to identify how best to structure health insurance and to deliver health care services is a central priority for comparative effectiveness research. Studies designed to evaluate these issues are frequently conducted in large insurance systems. We sought to describe the challenges faced when conducting trials in this context. METHODS: Using the Post-Myocardial Infarction Free Rx Event and Economic Evaluation (MI FREEE) trial as an example, we describe the methodological and practical challenges of conducting trials in large insurance systems. RESULTS: We encountered six key challenges while conducting MI FREEE trial, namely the need to obtain plan sponsor permission to experiment, the desire of plan sponsors to have all of their beneficiaries receive the same intervention, the inaccuracy of claims-based identification methods and the impact of claims lag on the timely enrollment of potentially eligible patients, the reluctance of patients to participate in insurance-based interventions and the potential need for informed consent, the frequent introduction of new cointerventions in real-world delivery systems, and the high rates of loss to follow-up because of insurance "churn." We describe the approaches we used to overcome these challenges. CONCLUSIONS: Studies in insurance settings are a powerful and necessary design for evaluating comparative effectiveness interventions. There are numerous strategies to address the potential logistical and methodological challenges that this research environment uniquely creates.