Normal mouse serum lipoproteins suppress a number of immunologic functions, such as mitogen stimulation, primary immune response, and allograft rejection in vivo. The effects of one class of lipoproteins, high density lipoprotein (HDL), were investigated after i.v. administration. Maximum suppression of spleen and peripheral blood lymphocyte (PBL) mitogen stimulation occurred when HDL was administered up to 8 hr before testing. Spleen cells remained suppressed 48 hr after injection, while PBL regained most of their activities. Injection of HDL 24 hr after sheep red blood cell (SRBC) immunization was as effective as giving HDL 8 hr before SRBC in suppressing primary immune response to SRBC. Induction of T cell allograft immunity was also suppressed by the injection of HDL.