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Between 1989 and 1992, the Agency for Health Care Policy and Research (A H C P R) awarded funding to 14 special projects known as Patient Outcomes Research Teams (PORTs). These large, complex projects form the centerpiece of the first generation of research under the Medical Treatment Effectiveness Program. In carrying out their individual 5-year research plans, and through collaborative work of six Inter-PORT Work Groups, PORTs have contributed to methodological advances related to their specific clinical focus and to outcomes research in general. Each of the PORTs has followed a standard research model, involving the application of: systematic literature review, measurement of outcomes, analysis of cost and claims data, decision analysis, and strategies for disseminating findings. This article reports what has been learned by individual PORTs, and by A H C P R, regarding the usefulness of each of these methodologies, both for the ongoing projects and for the next generation of effectiveness research. Examples from individual PORTs and work groups illustrate some of the methodological gains that have been made in effectiveness research and provide a glimpse of the work that remains to be done.