We recently reported that rabbit antithymocyte globulin was markedly inferior to horse antithymocyte globulin as primary treatment of severe aplastic anemia. Here we expand on our findings in this unique cohort of patients. Rabbit antithymocyte globulin was detectable in plasma for longer periods than horse antithymocyte globulin; rabbit antithymocyte globulin in plasma retained functional capacity to bind to lymphocytes for up to one month, horse antithymocyte globulin for only about two weeks. There were much lower numbers of neutrophils in patients treated with rabbit antithymocyte globulin than in patients with horse antithymocyte globulin in the first week post treatment. Both antithymocyte globulins induced 'cytokine storm' in the first two days after administration. Rabbit antithymocyte globulin was associated with higher levels of chemokine (C-C motif) ligand 4 during the first three weeks compared with horse antithymocyte globulin. Besides much lower absolute number and relative frequency of CD4+ T cells, rabbit antithymocyte globulin induced higher frequencies of CD4+CD38+, CD3+CD4-CD8- T cells, and B cells than horse antithymocyte globulin. Serum sickness occurred around two weeks after infusion of both types of antithymocyte globulin. Human anti-antithymocyte globulin antibodies, especially of the IgM subtype, correlated with serum sickness, which appeared concurrent with clearance of antithymocyte globulin in blood and with production of cytokines. In conclusion, rabbit and horse antithymocyte globulins have very different pharmacokinetics and effects on neutrophils, lymphocyte subsets, and cytokine release. These differences may be related to their efficacy in suppressing immune system and restoring hematopoiesis in bone marrow failure.