Aims This study evaluated the effectiveness of a brief intervention (BI) for illicit drugs (cannabis, cocaine, amphetamine-type stimulants and opioids) linked to the World Health Organization (WHO) Alcohol, Smoking and Substance Involvement Screening Test (ASSIST). The ASSIST screens for problem or risky use of 10 psychoactive substances, producing a score for each substance that falls into either a low-, moderate- or high-risk category. Design Prospective, randomized controlled trial in which participants were either assigned to a 3-month waiting-list control condition or received brief motivational counselling lasting an average of 13.8 minutes for the drug receiving the highest ASSIST score. Setting Primary health-care settings in four countries: Australia, Brazil, India and the United States. Participants A total of 731 males and females scoring within the moderate-risk range of the ASSIST for cannabis, cocaine, amphetamine-type stimulants or opioids. Measurements ASSIST-specific substance involvement scores for cannabis, stimulants or opioids and ASSIST total illicit substance involvement score at baseline and 3 months post-randomization. Findings Omnibus analyses indicated that those receiving the BI had significantly reduced scores for all measures, compared with control participants. Country-specific analyses showed that, with the exception of the site in the United States, BI participants had significantly lower ASSIST total illicit substance involvement scores at follow-up compared with the control participants. The sites in India and Brazil demonstrated a very strong brief intervention effect for cannabis scores (P<0.005 for both sites), as did the sites in Australia (P<0.005) and Brazil (P<0.01) for stimulant scores and the Indian site for opioid scores (P<0.01). Conclusions The Alcohol, Smoking and Substance Involvement Screening Test-linked brief intervention aimed at reducing illicit substance use and related risks is effective, at least in the short term, and the effect generalizes across countries.