Interviewing the family of a possible organ donor is a legal requirement in Spain, but it is the stage at which most potential donors are lost. Multiple factors influence the family's acceptance or rejection of this option, including awareness of the wishes of the deceased, personal preconceived attitudes of family members, as well as issues related to the hospital and its health care personnel, whose attitudes are a key factor in obtaining permission. We examined all 651 donation situations in a single hospital that included a family interview over the last 15 years. Among these 651 cases, 191 families refused donation (29.3%). The rate of donation refusal has fallen from 46.3% to 12.5% over these 15 years. To better understand the evolution of donor characteristics, interviewees, and the setting, we divided the sample into three 5-year periods to analyze key variables collected from the family interviews. The results showed that at the same time as the donor profile has changed, namely, fewer brain trauma cases and more victims of stroke as well as older mean age and more coexistent diseases, these has been an improvement in the factors related to the information and opinion of both the families and the donor about this process. The main reasons for refusal of donation have changed from negation of brain death, religious factors, and the desire to maintain the body intact during the 1990s, to sociocultural reasons in minority ethnic groups, to presumed refusal during life, and to family disagreements during the more recent years.