The World Health Organization estimates that, by 2020, the number of Americans affected by at least one chronic condition requiring medication therapy will grow to 157 million. Effective medications are a cornerstone of prevention and disease treatment, yet only about half of patients take their medications as prescribed, resulting in a common and costly public health challenge for the U.S. health care system. As with much of health care, drug adherence is primarily about human behavior. Therefore, patients who lack motivation to take their medication as prescribed cannot be forced or simply educated to take their medication; they must be persuaded and motivated to do so. However, existing literature on how persuasion-based behavioral change can be achieved for non-adherent patients is sparse. To help build more evidence on how effective communication can be used to promote drug adherence for patients who have been diagnosed with chronic illness, this research tested the effectiveness of counterfactual thinking as a message design strategy aimed at increasing drug adherence among individuals at risk for nonadherence. Findings from experiments 1 and 2 showed no effect of counterfactual thinking on medication adherence. Findings from experiment 3 showed that, in a sample of 303 patients with type 2 diabetes at risk for nonadherence, messages including upward counterfactual thinking (e.g., “if only I had taken my medication as prescribed, I would not be in the hospital right now!”), compared to messages including downward counterfactual thinking (e.g., “it could have been worse and I could have died!”) or no counterfactual thinking, increased perceptions of medication adherence self- and response efficacy, and behavioral intention to take one’s medications as prescribed. Counterfactual thinking-based messages are a promising and easy to use persuasion strategy for patients who are at risk for nonadherence. Counterfactual thinking can be incorporated in interventions aimed at increasing adherence, and in doctor-patient or pharmacist-patient communications. Future studies should replicate these findings patients who have other chronic illnesses. Furthermore, measuring actual medication adherence behavior as opposed to behavioral intention, would provide a better indicator of the effectiveness of counterfactual thinking in increasing adherence.