Mindfulness based interventions have been shown to be efficacious in treating depression, anxiety, pain and substance use disorders (SUDs). Mindfulness-Based Relapse Prevention (MBRP) is an intervention that integrates cognitive-behavioral relapse prevention and mindfulness meditation practices, in an 8-week, manualized group intervention designed to treat SUDs by helping patients regulate negative emotional states and reactive behavior. This paper describes the rationale, study design and methodology of a two-site, randomized controlled trial comparing MBRP to 12-Step Facilitation (TSF) in military Veterans following completion of intensive outpatient treatment for SUDs. The 8 weeks of 90-min, group-based MBRP or TSF sessions are followed by 3-, 6- and 10-month follow-up period with assessments of alcohol/drug use, quality of life, depression, anxiety, mindfulness and other functional outcomes, such as employment. The primary hypothesis is that MBRP will be significantly better than TSF in promoting recovery and prevention of relapse to substance use in a military Veteran population. The secondary hypothesis is that MBRP will lead to greater improvements in quality of life, depression/anxiety, and functional outcomes, such as employment. This study is designed to provide information about the use of group-based MBRP as a relapse prevention strategy for military Veterans who have completed an intensive SUD clinical treatment program. Clinical Trial Identifier: NCT02326363.