Background Antisocial personality disorder (ASPD), although associated with very significant health and social burden, is an under-researched mental disorder for which clinically effective and cost-effective treatment methods are urgently needed. No intervention has been established for prevention or as the treatment of choice for this disorder. Mentalization-based treatment (MBT) is a psychotherapeutic treatment that has shown some promising preliminary results for reducing personality disorder symptomatology by specifically targeting the ability to recognize and understand the mental states of oneself and others, an ability that is compromised in people with ASPD. This paper describes the protocol of a multi-site RCT designed to test the effectiveness and cost-effectiveness of MBT for reducing aggression and alleviating the wider symptoms of ASPD in male offenders subject to probation supervision who fulfil diagnostic criteria for ASPD. Methods Three hundred and two participants recruited from a pool of offenders subject to statutory supervision by the National Probation Service at 13 sites across the UK will be randomized on a 1:1 basis to 12 months of probation plus MBT or standard probation as usual, with follow-up to 24 months post-randomization. The primary outcome is frequency of aggressive antisocial behaviour as assessed by the Overt Aggression Scale – Modified. Secondary outcomes include violence, offending rates, alcohol use, drug use, mental health status, quality of life, and total service use costs. Data will be gathered from police and criminal justice databases, NHS record linkage, and interviews and self-report measures administered to participants. Primary analysis will be on an intent-to-treat basis; per-protocol analysis will be undertaken as secondary analysis. The primary outcome will be analysed using hierarchical mixed-effects linear regression. Secondary outcomes will be analysed using mixed-effects linear regression, mixed-effects logistic regression, and mixed-effects Poisson models for secondary outcomes depending on whether the outcome is continuous, binary, or count data. A cost-effectiveness and cost-utility analysis will be undertaken. Discussion This definitive, national, multi-site trial is of sufficient size to evaluate MBT to inform policymakers, service commissioners, clinicians, and service users about its potential to treat offenders with ASPD and the likely impact on the population at risk.