Germ-free and conventional mice were fed sterile peptidoglycan-polysaccharide polymers to determine whether intestinal bacterial cell wall products influence systemic immunity. Germ-free mice fed saline had significantly less footpad swelling after challenge with sheep erythrocytes than conventional mice. Feeding peptidoglycan-polysaccharide polymers to germ-free mice restored their deficient cellular immune response to conventional levels. Feeding peptidoglycan-polysaccharide did not alter anti-erythrocyte antibody production in germ-free mice. Spontaneous in vitro proliferation of unfractionated splenocytes taken from germ-free mice fed peptidoglycan-polysaccharide polymers was enhanced compared with proliferation of splenocytes from germ-free mice fed human serum albumin. In vitro conconavalin A stimulation of unfractionated splenocytes obtained from germ-free mice fed cell wall polymers resulted in a significant decrease in proliferation relative to that seen for germ-free mice fed human serum albumin. Respective proliferation results were abrogated when splenocytes were fractionated by removal of plastic-adherent cells. These results suggest that luminal peptidoglycan-polysaccharide polymers are important in the functional development of systemic cellular immunity, and that plastic-adherent splenocytes regulate this response.