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Aims Mental health-related stigma is a major challenge associated with the huge mental health treatment gap. It has remained unclear what kind of educational content is effective in reducing the stigma. Whether biomedical messages (BMM) about mental illness are effective or harmful in decreasing stigma is controversial. To investigate whether BMM can improve practically useful knowledge of mental illness, comparably to recommended messages (RCM) advocated by experts, of types such as ‘recovery-oriented’, ‘social inclusion/human rights’ and ‘high prevalence of mental illnesses’ through a randomised controlled trial (RCT). Method This study is an individual-level RCT with a parallel-group design over 1 year, conducted in Tokyo, Japan. A total of 179 participants (males n = 80, mean age = 21.9 years and s.d. = 7.8) were recruited in high schools and universities, and through a commercial internet advertisement in June and July 2017, without any indication that the study appertained to mental health. Participants were allocated to the BMM and RCM groups. They underwent a 10-min intervention, and completed self-report questionnaires during baseline, post-test, 1-month follow-up and 1-year follow-up surveys. The primary outcome measures were practically useful knowledge of mental illness at the post-test survey using the Mental Illness and Disorder Understanding Scale (MIDUS). Analysis was conducted in October 2018. Results Both groups demonstrated improved MIDUS score in the post-test survey, and showed similar intervention effects (F(1, 177) = 160.5, p < 0.001, η2 = 0.48). The effect of the interventions continued until the 1-year follow-up survey (B [95% CI] = −2.56 [−4.27, −0.85], p < 0.01), and showed no difference between groups. The reported adverse effect that BMM increase stigma was not confirmed. Conclusions BMM may have a positive impact on stigma, comparable to RCM. These findings may encourage reconsideration of the content of messages about mental health, as it is indicated that combining BMM and RCM might contribute to an effective anti-stigma programme.