Because autologous donation is permitted for donors who do not meet homologous blood donation standards, referring physicians and blood center personnel may be concerned about autologous donor reactions. Small studies have determined that mild reactions do not occur more frequently, but the incidence of rarer, more serious, moderate and severe reactions is unknown. We therefore studied the frequency of reactions during 10,200 autologous and 219,307 concurrent homologous donations at four blood centers. No significant difference was seen for severe reactions: autologous 0.039% (4/10,200), homologous 0.037% (82/219,307) (p = 0.79); moderate reactions: autologous 0.19% (19/ 10,200), homologous 0.22% (473/219,307) (p = 0.60) or mild reactions: autologous 2.26% (231/10,200), homologous 2.26% (4946/219,307) (p = 0.98). We conclude moderate and severe donation reactions do not occur more frequently among autologous donors who are preselected by referring physicians and screened by blood center personnel.