The aim of this study was to evaluate the effects of repeated oronasal administration of lipopolysaccharide (LPS) on milk composition and the overall productive performance of dairy cows. One hundred pregnant Holstein dairy cows were randomly assigned to two treatment groups (n = 50). 30 cows out of 100 were selected for intensive sampling (n = 15) starting at 28 d before parturition. Cows were administered orally and nasally with 2 and 1 mL of saline solution, respectively (control), or saline solution containing 3 doses of LPS from Escherichia coli 0111:B4 as follows: 1) 0.01 μg/kg body weight (BW) on d ﹣28, 2) 0.05 μg/kg BW on d ﹣25 and ﹣21, and 3) 0.1 μg/kg BW on d ﹣18 and ﹣14. Daily feed intake and milk production were recorded for each cow during the first 28 d postpartum. Milk samples were obtained once per week and analyzed for various milk components. Overall, results indicated that treatment did not affect feed intake, milk yield, milk efficiency, fat content, fat yield, protein content, protein yield, lactose content, lactose yield, milk urea nitrogen (MUN), total solid contents, fat-corrected milk (FCM), and energy-corrected milk (ECM; P > 0.05). However, milk somatic cell count (SCC) tended to be lower in the treated cows (P < 0.10). Treated primiparous cows showed tendencies for better milk efficiency (P < 0.10), milk-fat content (P = 0.09), and total solid contents (P = 0.06). There was a treatment by week interaction for milk energy (P = 0.03), and tendencies for FCM, ECM, lactose content, and milk efficiency (P < 0.10) with greater values in the treated primiparous animals. Altogether, results of this study showed that oronasal LPS challenges slightly modulated milk composition of periparturient dairy cows.