The two most widely used stress reduction programs are MBSR and the Relaxation Response (RR). Although both programs use meditation techniques and effectively reduce stress, proponents of each program postulate very different mechanistic models. We hypothesized that there would be both shared and unique neural mechanisms associated with each program, as well as differential psychological and physiological mechanisms. To test these hypotheses, we performed an RCT in collaboration with the Center for Mindfulness and the Benson-Henry Institute. Healthy but stressed individuals were randomized to MBSR or the Relaxation Response. Differential brain activity during meditation was observed in each group, as well as group differences in breathing rate. Group differences in resting brain activity and change in rumination and self-compassion were also observed. There were no group differences in mindfulness as assessed by the FFMQ. The results suggest that MBSR and the RR reduce stress in different ways.