Transition dairy cows experience a high incidence of metabolic and infectious diseases immediately after calving. Recent research implicates bacterial lipopolysaccharide (LPS) and lipoteichoic acid (LTA) in their pathogenesis. Minimal knowledge exists of the periparturient dairy cow immune response to oral endotoxin exposure while other routes have been extensively explored. The objective of this study was to evaluate the humoral immune response of periparturient dairy cows to repeated oral administration of LPS and LTA alone or in combination with subcutaneous injections. Two hundred dairy cows were randomly assigned to one of 4 treatments (n = 50 per group; administration d −28, −25, −21, −18, and −14 before expected calving date): 1) 2 mL oral sterile saline (CON), 2) Flat doses of oral LPS and LTA (TRT1), 3) Flat doses of oral LPS and LTA plus subcutaneous (sc) injection d −18 and −14 (TRT2), 4) Oral increasing doses of LPS at 6.5 µg (d −28 and −25), 32.5 µg (d −21 and −18) and 65 µg (d −14), all with flat doses of LTA (TRT3). Flat doses of LPS and LTA were 100 and 120 µg/cow, respectively, in 2 mL sterile saline. Blood samples collected from the coccygeal vein at d −28, −7, +7, and +28 were analyzed for lipopolysaccharide binding protein (LBP), interleukin 1 (IL-1), transforming growth factor-β (TGF-β), immunoglobulin M (IgM), and immunoglobulin G (IgG). Statistical results showed there was no effect of treatment on serum concentrations of LBP (P = 0.82), IL-1 (P = 0.50), TGF-β (P = 0.75), IgG (P = 0.25), or IgM (P = 0.40). Overall, preliminary results suggest that repeated oral administration of LPS and LTA or in combination with sc injections did not modulate humoral immunity in periparturient dairy cows.