Objective: This study aimed to determine whether the practice of mindfulness reduces the level of stress experienced by senior medical students. Methods: We carried out a multicentre, single-blinded, randomised controlled trial with intention-to-treat analysis in three clinical schools attached to the University of Tasmania, Hobart, Tasmania. Participants included 66 medical students in their final 2years of study in 2009. Participants were block-randomised to either an intervention or a usual care control group. The intervention used an audio CD of guided mindfulness practice designed and produced for this trial. Participants were advised to use the intervention daily over the 8weeks of the trial. All participants completed two self-report questionnaires, at baseline and at 8weeks, respectively. The intervention group also completed a questionnaire at 16weeks to provide follow-up data. The primary outcome measure was the difference over time in scores on the Perceived Stress Scale (PSS). The secondary outcome measure referred to differences over time in scores on the subscales of the Depression, Anxiety and Stress Scale (DASS). Results: Mean baseline scores on the PSS and the stress component of the DASS were 15.7 (maximal score of 40) and 13.2 (maximal score of 42), respectively, both of which exceed scores in age-matched normative control data. Using multivariable analysis, participants in the intervention group demonstrated significant reductions in scores on the PSS (-3.44, 95% confidence interval [CI] -6.20 to -0.68; p<0.05) and the anxiety component of the DASS (-2.82, 95% CI -4.99 to -0.64; p<0.05). A borderline significant effect was demonstrated on the stress component of the DASS (-3.69, 95% CI -7.38 to 0.01; p=0.05). Follow-up at 8weeks post-trial revealed that the effect was maintained. Conclusions: Mindfulness practice reduced stress and anxiety in senior medical students. Stress is prevalent in medical students and can have adverse effects on both student health and patients. A simple, self-administered, evidence-based intervention now exists to manage stress in this at-risk population and should be widely utilised.