The immune response of adult rabbits to daily doses of horse γ-globulin (HoGG) administered intravenously or intramuscularly in various tolerance-inducing regimens was investigated. Circulating HoGG, anti-HoGG antibodies, and hemolytic complement (C) levels were measured daily. High dose tolerance, as defined by antigen elimination, was achieved by both routes with 100, but not 10, mg HoGG/kg body weight/day. There was an initial accumulation of large amounts of HoGG during the 1st week. The HoGG titer decreased markedly during weeks 2 and 3 in association with the appearance of agglutinating and precipitating anti-HoGG antibody in most of the animals. However, by the 4th week detectable antibody formation against certain of the HoGG antigens ceased and the HoGG concentration again began to rise. Antibodies to at least one HoGG antigen persisted while ‘tolerance’ to at least two other HoGG antigens had been induced. Serum C levels showed close correlation with HoGG levels, such that marked hypocomplementemia was seen during the immune phase of weeks 2 and 3, and normal or elevated C levels were observed when HoGG levels rose to the high ‘tolerant’ values. Pretreatment with centrifuged deaggregated HoGG 7 days prior to the daily regime led to accumulation of each of the 3 HoGG antigens without a demonstrable immune phase; antigen levels constantly were high, circulating antibodies could not be detected and hypocomplementemia was avoided. Administration of horse anti-rabbit lymphocyte serum in association with HoGG led to a greatly increased catabolism of the HoGG, an early appearance of anti-HoGG antibodies and absence of tolerance to any HoGG antigens. These observations add descriptive data on the interplay between antigen, antibody and C during the induction of high-dose tolerance, and have aided in interpreting the response of humans to HoGG and horse anti-lymphocyte globulin (HoALG). They are consistent with the hypothesis that dosages of HoGG commonly used in the administration of HoALG to man favor the induction of tolerance to HoGG via the mechanism of ‘immunologic paralysis’ or ‘high-dose tolerance’.