Objectives <p>Mindfulness-based relapse prevention (MBRP) incorporating cognitive behavioral therapy (CBT) has been assessed as effective in treating substance use and drug relapse prevention. In Hong Kong, evidence-based research examining the validity and application of a mindfulness approach in drug relapse prevention remains rare. This study was conducted to assess the feasibility and efficacy of the MBRP program in drug relapse prevention for young people aged 14–35 years&#xa0;with psychotropic substance use compared with a CBT program administered in a community outpatient setting.</p> Method <p>This study used a randomized controlled trial with pre-, post-, and 4-month follow-up with a quantitative questionnaire and qualitative in-depth interviews with each participant. A total of five MBRP and four CBT groups were run with 29 and 23 registered participants, respectively.</p> Results <p>The quantitative and qualitative results showed that the MBRP program was effective, particularly its short-term and immediate effects on the participants’ drug use severity, confidence in refusing drugs, and mindful responses in observing their body sensations and noticing their drug-taking needs with acceptance and non-reactance. However, they could not maintain daily mindfulness practice at home. The long-term and sustainable effects of the program were mitigated.</p> Conclusions <p>To further enhance the MBRP program’s efficacy in drug relapse prevention, the right balance between allowing participants to describe and be aware of their body sensations and integration with other approaches such as the meaning-centered approach should be further examined.</p> Preregistration <p>This study is not preregistered.</p>