Summary Migraine is the world's second leading cause of disability; half of the 45 million Americans with migraine require bedrest for relief. Migraine affects overall health, relationships, careers, and financial stability. Disability is a patient-centered outcome that captures the full impact of disease on patients' lives. Migraine medications are limited by side effects, lack of efficacy, and costs. Despite recommendations against opioid use due to risks of medication overuse headache and addiction, a third of Americans with migraine turn to opioids for acute relief. There is an unmet need for more effective migraine therapies that target disability with long-term efficacy, safety, and tolerability. Mindfulness-based stress reduction (MBSR) can help migraine as it targets stress, the top migraine trigger. Mindfulness may change the pain experience through brain mechanisms associated with nociceptive processing, cognitive function, and emotional regulation. We have shown mindfulness has statistically significant and clinically meaningful benefits on disability, pain catastrophizing, depression, and self-efficacy in patients with migraine. Interceptive awareness and headache frequency also improved. Our prior research utilized designs with high methodological rigor (e.g., RCT) but were modest in size with homogenous samples of participants able to engage with in-person classes that limited generalizability. Such limitations may be offset by flexible online options. Patients with migraine are interested in electronic (e)Health options, yet few evidenced-based options exist. This proposal addresses these gaps with a large study using national recruitment and an online, accessible intervention that was developed to deliver key mindfulness principles to diverse populations. We plan to test the efficacy of online MBSR vs. online HA education in adults with migraine in a phase 3 RCT. The main goal will be evaluation of efficacy (Aim 1), with secondary goals of understanding mechanisms (Aim 2) and gathering data (Aim 3) for a future, scalable implementation study. As done previously, interventions will be matched on time/attention and participants will continue all current migraine medications, as we have shown medication plus behavioral treatments have the greatest impact. This fully remotely delivered study will determine the efficacy of online MBSR in adults with migraine to target the urgent need for better migraine treatments on the patient-centered outcome of migraine disability. We are using an eHealth delivery format that increases access and availability to diverse populations compared to in- person weekly classes. Mind-body treatments can be leveraged to advance health equity and we will do so through a variety of strategies. If effective, this research will lead to an implementation trial so that ultimately, patients with migraine of diverse backgrounds will have an easily accessible, standardized, non-drug, non- opioid treatment that could ...