A small group of frequent emergency department visitors account for a disproportionally large fraction of health care consumption, including unplanned hospitalizations and overall healthcare costs. In response, case and disease management programs aimed at reducing health care consumption in this group have been tested, however results vary widely. In this study, we aimed to investigate if a telephone-based, nurse led case management intervention can reduce health care consumption for frequent emergency department visitors in a large-scale set-up. A total of 12,181 frequent emergency department users in three counties in Sweden were randomized either using Zelen's design or a traditional randomized design to receive a nurse led case management intervention or no intervention. Patients were followed for health care consumption for up to 2 years. The results of the study with traditional design showed an overall 12% (95% confidence interval [CI], 4-19%) decreased rate of hospitalization, which was mostly driven by effects among patients included in the last year. Similar results were achieved in the Zelen studies, with significant reduction of hospitalization, again in the last year, but mixed results in the early development of the project. Our study provides evidence that a carefully designed telephone-based intervention with accurate and systematic patient selection and appropriate staff training in a centralized set-up can lead to significant decreases in health care consumption and costs. However, we also demonstrate that the effects are sensitive to the delivery model chosen.