Objective: Generalist health professional training on substance abuse prevention is patchy. This study assessed the effects of Project MAINSTREAM, a national interdisciplinary faculty development fellowship program, whose principal objective was to enhance curriculum on basic substance abuse services at health professions training institutions. Five interdisciplinary teams of three health professions' faculty were selected as fellows. This study assessed changes in curriculum, training, fellows' knowledge, and fellows' academic productivity in substance abuse. Design: Pre and post-program surveys and interviews were administered. Setting: Fellows were located in five cities in the USA. Method: The two-year, part-time training program featured training meetings, on-site and distance mentoring, and internet-based instructional materials. Principal learning activities consisted of developing independent projects in curriculum enhancement and prevention services delivery. Results: Fellows implemented 45 distinct curricula, providing 19,000 hours of new instruction to over 5000 trainees. Over 80 per cent of the training occurred as required curricular experiences. Fellows' academic accomplishments included five peer-reviewed publications, seven additional submitted papers, 78 presentations, and 23 awards or appointments. Fellows' knowledge increased significantly. Conclusions: Project MAINSTREAM shows promise as a national model for enhancing health professional training on substance abuse. (Contains 4 tables and 1 figure.)