Low-density lipoprotein apheresis (LDL-apheresis) is an extracorporeal procedure that preferentially removes LDL cholesterol from the blood. One of the primary techniques for performing this procedure uses immunoadsorption columns containing monospecific polyclonal sheep antibodies to human LDL covalently coupled to a gel filtration medium. LDL-apheresis has generally been well-tolerated, with chills, fever, or flushing occurring rarely. The possibility of an immune reaction was investigated as a basis for these reactions observed in 12 of the 1312 procedures performed. Antibodies to sheep IgG developed in 12 of the 15 patients treated with LDL-apheresis as a result of the shedding of small quantities of the sheep immunoglobulin from the columns. A column acid-washing procedure minimized the quantity of shed antibody but did not prevent immunization of the patient. The clinical reactions were probably unrelated to shedding and immunization, as the reactions occurred even in patients who were not immunized to the sheep IgG. Immunization to ethylene oxide was not the cause, as determined by a radioallergosorbent test. The reactions were more likely related to the activation of complement, as indicated by the generation of C3a des Arg by the columns and an increase in C3a des Arg levels systemically.