A substantial number of opiate dependent patients does not benefit sufficiently from methadone based treatment. Aim of this study was to explore the effectiveness of heroin-assisted treatment in methadone patients who continue intravenous heroin use and in heroin dependent patients currently not in treatment. The trial was designed as an open-label multi-centre randomised controlled study, 1,015 heroin dependent patients, either continuing intravenous heroin use while on methadone maintenance or currently not in treatment, received a variable dose of either injectable heroin (N=515) or oral methadone (N=500) for 12 months. In an ITT analysis, two response criteria, improvement of physical and/or mental health and decrease in illicit drug use, were used. Retention was higher in the heroin (67.2%) than in the methadone group (40.0%) and the heroin group showed a significantly greater response than the methadone group on both primary outcome measures. More SAEs related to the medication were found in the heroin group, mainly associated to the intravenous use of the substance. Heroin-assisted treatment is more effective than methadone maintenance treatment for opioid dependent persons who continue intravenous heroin use while on methadone maintenance or who are not enrolled in treatment. Despite a higher risk, it should be considered as an option for these treatment resistant patients provided it is administered under medically supervised conditions.