BACKGROUND: College students and working adults are particularly vulnerable to stress and other mental health problems, and mental health promotion and prevention are needed to promote their mental health. In recent decades, mindfulness-based training has demonstrated to be efficacious in treating physical and psychological conditions. OBJECTIVE: The aim of our study was to examine the efficacy of an Internet-based mindfulness training program (iMIND) in comparison with the well-established Internet-based cognitive-behavioral training program (iCBT) in promoting mental health among college students and young working adults. METHODS: This study was a 2-arm, unblinded, randomized controlled trial comparing iMIND with iCBT. Participants were recruited online and offline via mass emails, advertisements in newspapers and magazines, announcement and leaflets in primary care clinics, and social networking sites. Eligible participants were randomized into either the iMIND (n=604) or the iCBT (n=651) condition. Participants received 8 Web-based sessions with information and exercises related to mindfulness or cognitive-behavioral principles. Telephone or email support was provided by trained first tier supporters who were supervised by the study's research team. Primary outcomes included mental and physical health-related measures, which were self-assessed online at preprogram, postprogram, and 3-month follow-up. RESULTS: Among the 1255 study participants, 213 and 127 completed the post- and 3-month follow-up assessment, respectively. Missing data were treated using restricted maximum likelihood estimation. Both iMIND (n=604) and iCBT (n=651) were efficacious in improving mental health, psychological distress, life satisfaction, sleep disturbance, and energy level. CONCLUSIONS: Both Internet-based mental health programs showed potential in improving the mental health from pre- to postassessment, and such improvement was sustained at the 3-month follow-up. The high attrition rate in this study suggests the need for refinement in future technology-based psychological programs. Mental health professionals need to team up with experts in information technology to increase personalization of Web-based interventions to enhance adherence. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR): ChiCTR-TRC-12002623; https://www2.ccrb.cuhk.edu.hk/ registry/public/191 (Archived by WebCite at http://www.webcitation.org/6kxt8DjM4).