Aims: The present study sought to replicate and extend a small pilot study conducted by Baker, Boggs & Lewin (2001) which demonstrated that brief interventions consisting of motivational interviewing and cognitive-behaviour therapy (CBT) were feasible and associated with better outcomes compared with a control condition. Design: Randomized controlled trial (RCT). Setting: Greater Brisbane Region of Queensland and Newcastle, NSW, Australia. Participants: The study was conducted among 214 regular amphetamine users. Measurements: Demographic characteristics, past and present alcohol and other drug use and mental health, treatment, amphetamine-related harms and severity of dependence. Findings: The main finding of this study was that there was a significant increase in the likelihood of abstinence from amphetamines among those receiving two or more treatment sessions. In addition, the number of treatment sessions attended had a significant short-term beneficial effect on level of depression. There were no intervention effects on any other variables (HIV risk-taking, crime, social functioning and health). Overall, there was a marked reduction in amphetamine use among this sample over time and, apart from abstinence rates and short-term effects on depression level, this was not differential by treatment group. Reduction in amphetamine use was accompanied by significant improvements in stage of change, benzodiazepine use, tobacco smoking, polydrug use, injecting risk-taking behaviour, criminal activity level, and psychiatric distress and depression level. Conclusions: A stepped-care approach is recommended. The first step in providing an effective intervention among many regular amphetamine users, particularly those attending non-treatment settings, may include provision of: a structured assessment of amphetamine use and related problems; self-help material; and regular monitoring of amphetamine use and related harms. Regular amphetamine users who present to treatment settings could be offered two sessions of CBT, while people with moderate to severe levels of depression may best be offered four sessions of CBT for amphetamine use from the outset, with further treatment for amphetamine use and/or depression depending on response. Pharmacotherapy and/or longer-term psychotherapy may be suitable for non-responders. An RCT of a stepped-care approach among regular amphetamine users is suggested.