Work-related stress is an increasing problem for knowledge workers, despite employee control and influence. As a consequence, the knowledge industry has expressed the need for new knowledge and approaches regarding how to support sustainable preventive action and assure productivity and well-being. A healthy organization has its starting point in the organization, and with a salutogenic approach, focus is on how the organization and work system can be designed in order to improve productivity and working conditions for the individuals involved. Two consecutive research and development projects building on a mixed-method approach have been conducted where organizational- level interventions were implemented in 10 knowledge-intensive companies. The aim was to re-design the daily work practices by using a multi-level, participatory and salutogenic approach. Participants from multi-organizational levels were thus seen as an integrated part of the whole process, including development, design and implementation, and not merely objects exposed to the intervention. The springboard for the changes was thus the local, shared understanding of the workplace and the externalization of individual knowledge regarding problems and potential solutions. The findings suggest that it is possible to prevent work-related stress in knowledge work by adapting a multi-level, collaborative and participatory model which comprises a set of approaches, capabilities and activities that we find to be of key importance in primary interventions. These include managerial support, externalization of tacit knowledge, collective evaluations, adjustments and decisions, visualization of progress and current status, appointed facilitators and a number of defined phases and activities.