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To identify those factors that enhance or inhibit organ donation in order to provide data to help policy makers, hospital administrators and transplantation professionals make informed choices about how to modify the donor system and to structure 'best practice' interventions.Legislative efforts to increase donation rates have not been successful. An emphasis on process is needed to help explain this.The study was conducted using a stratified random sample of 23 hospitals in the Pittsburgh and Minneapolis/St Paul standard statistical metropolitan areas. Each week, the medical charts of all in-patient and emergency room patient deaths at each hospital were reviewed using a standardized review protocol to determine eligibility for organ, tissue, and cornea donation. A total of 10681 patient charts were reviewed over a 4-yr period. Eight hundred and twenty-eight cases out of 1723 eligible cases were selected for inclusion in the study. Data were collected on 827 of these cases. All health care providers (HCPs) who spoke with the family after the patient's death or discussed donation with the family were interviewed.Of the 10681 patient charts reviewed, 16.5% were eligible to donate either organs, tissues, or corneas, and 87.0% of donor-eligible patients' families were approached and asked to donate. Consent rates were 23.5% for corneas, 34.5% for tissues, and 46.5% for organ donation. Multiple logistic regression demonstrated that the best and strongest predictor of donation decisions was the family's initial response to the donation request, as reported by the HCP. Three initial response groups are examined and compared. Those families who expressed an initially favorable reaction were most likely to agree to donation. Furthermore, discussion patterns differed by initial reaction group, with families who expressed initial indecision about donation sharing more characteristics with families who were not favorable than those who were favorable. More detailed information was provided to the favorable families, as compared to the other two groups, concerning the effect of donation on funeral arrangements and costs. Families who were favorable were also more likely to meet with an organ procurement organization representative than were other families. The strongest predictor of a family's unfavorable response to a donation request was the belief that the patient would have been against donation. A number of other variables, including HCP attitudes, also had an impact on the family's decision to donate.A number of discussion and HCP characteristics are associated with a family's willingness to consent to organ donation. Further study is needed to determine if interventions based on the characteristics identified in this study will increase consent to donation.