BACKGROUND: Work-related musculoskeletal disorders (WMSD) represent a major public health problem and economic burden to employers, workers and health insurance systems. This systematic review had two objectives: (1) to analyze the cost-benefit results of organizational-level ergonomic workplace-based interventions aimed at preventing WMSD, (2) to explore factors related to the implementation process of these interventions (obstacles and facilitating factors) in order to identify whether economic results may be due to a successful or unsuccessful implementation. METHODS: Systematic review. Studies were searched in eight electronic databases and in reference lists of included studies. Companion papers were identified through backward and forward citation tracking. A quality assessment tool was developed following guidelines available in the literature. An integration of quantitative economic results and qualitative implementation data was conducted following an explanatory sequential design. RESULTS: Out of 189 records, nine studies met selection criteria and were included in our review. Out of nine included studies, grouped into four types of interventions, seven yielded positive economic results, one produced a negative result and one mixed results (negative cost-effectiveness and positive net benefit). However, the level of evidence was limited for the four types of interventions given the quality and the limited number of studies identified. Our review shows that among the nine included studies, negative and mixed economic results were observed when the dose delivered and received by participants was low, when the support from top and/or middle management was limited either due to limited participation of supervisors in training sessions or a lack of financial resources and when adequacy of intervention to workers' needs was low. In studies where economic results were positive, implementation data showed strong support from supervisors and a high rate of employee participation. CONCLUSION: Studies investigating the determinants of financial outcomes of prevention related to implementation process are very seldom. We recommend that in future research economic evaluation should include information on the implementation process in order to permit the interpretation of economic results and enhance the generalizability of results. This is also necessary for knowledge transfer and utilization of research results for prevention-oriented decision-making in occupational health and safety.