We aimed to evaluate the efficacy of an enhanced mindfulness based stress reduction (MBSR+) versus stress management for headache (SMH). We performed a randomized, assessor-blind, clinical trial of 98 adults with episodic migraine recruited at a single academic center comparing MBSR+ (n=50) to SMH (n=48). MBSR+ and SMH were delivered weekly by group for 8 weeks, then bi-weekly for another 8 weeks. The primary clinical outcome was reduction in headache days from baseline to 20 weeks. MRI outcomes included activity of left dorsolateral prefrontal cortex (DLPFC) and cognitive task network during cognitive challenge, resting state connectivity of right dorsal anterior insula (daINS) to DLPFC and cognitive task network, and gray matter volume of DLPFC, daINS, and anterior midcingulate. Secondary outcomes were headache-related disability, pain severity, response to treatment, migraine days, and MRI whole-brain analyses. Reduction in headache days from baseline to 20 weeks was greater for MBSR+ (7.8 [95%CI, 6.9-8.8] to 4.6 [95%CI, 3.7-5.6]) than for SMH (7.7 [95%CI 6.7-8.7] to 6.0 [95%CI, 4.9-7.0]) (P=0.04). 52% of the MBSR+ group showed a response to treatment (50% reduction in headache days) compared with 23% in the SMH group (P=0.004). Reduction in headache-related disability was greater for MBSR+ (59.6 [95%CI, 57.9-61.3] to 54.6 [95%CI, 52.9-56.4]) than SMH (59.6 [95%CI, 57.7-61.5] to 57.5 [95%CI, 55.5-59.4]) (P=0.02). There were no differences in clinical outcomes at 52 weeks or MRI outcomes at 20 weeks, although changes related to cognitive networks with MBSR+ were observed. MBSR+ is an effective treatment option for episodic migraine.