The safety of autologous blood donation by "high-risk" patients (those with some preexisting medical conditions) has been questioned. The authors reviewed 1393 consecutive blood donation records (207 high-risk autologous [HRA], 665 non-high-risk autologous [NHRA], and 521 directed donors [DD]) to determine the safety and outcome of blood donation by HRA patients as compared with other donors at their center. The HRA group included patients with a history of significant coronary artery on cerebral vascular disease, recent seizures, cardiac arrhythmia, chronic heart failure, valvular or congenital heart disease, symptomatic dyspnea, insulin-dependent diabetes and/or current therapy with two or more antihypertensive medications. Those designated NHRA were all other autologous donors; DD met all criteria for homologous donation. Donor characteristics including predonation hematocrit, pre- and postdonation mean arterial pressure and heart rates were similar in all groups. Eight HRA donors (3.9%) had reactions, compared with 21 NHRA (3.2%) and 23 DD (4.4%), a difference that was without statistical significance. The reaction rate in all autologous donors (HRA and NHRA) was 3.4%. No differences in symptoms reported, hemodynamics or reaction severity were observed among the three groups (P > .05). A multiple logistic regression was performed within and among the groups with the risk factor categories listed above and medication classes including beta blockers, cardiac glycosides, calcium-channel blockers, antihypertensive agents, nitrates, and antiarrhythmic agents (chi 2 = 14.9; P = .0006). Only first-time donation (P = .0001) and cardiac glycoside usage (P = .04) were positively associated with an untoward reaction. The authors conclude that donation by HRA donors is at least as safe as that by donors who meet homologous donation criteria in their population and setting.