Immunoactivation via a lipopolysaccharide [LPS] bolus negatively affects multiple productive parameters in farm animals. However, the paradigm of acute LPS bolus likely does not resemble chronic on-farm in vivo immunoactivation. Therefore, study objectives were to characterize the effects of chronic inflammation on production in lactating Holstein cows. Eleven cows (164 ± 22 DIM; 676 ± 16 kg BW; parity 3.1 ± 0.4) were acclimated for 3 d, and subjected to 2 periods (P); during P1 (3 d), cows consumed feed ad-libitum and baseline samples were obtained. During P2 (7 d), cows were assigned to 1 of 2 treatments: (1) saline-infused and pair-fed (CON-PF; 40 mL/h saline; n = 5) or (2) LPS-infused and ad libitum-fed (LPS-AL; E. coli O55:B5; 0.017, 0.020, 0.026, 0.036, 0.055, 0.088, and 0.148 μg/kg BW/h d1–7, respectively; n = 6). CON-PF cows were pair-fed to eliminate confounding effects of dissimilar nutrient intake. LPS induced a febrile response in LPS-AL cows on d 1 (+0.49°C) relative to baseline and LPS-AL cows remained hyperthermic for the remainder of P2 (+0.26°C; P < 0.01). Relative to CON-PF, respiration rate and heart rates increased 17 breathes per min and 11 beats per min, respectively, during P2 (P < 0.01) for LPS-AL cows. DMI decreased (28%; P < 0.05) on d 1 as a result of LPS, but DMI progressively increased with time (P < 0.01) returning to baseline levels after 6 d; by design, the CON-PF cows DMI pattern mirrored LPS-AL cows. Relative to baseline and CON-PF cows, milk yield from LPS-AL cows decreased 17% on P2D1 (P = 0.01). From P2D2 onwards, milk yield from both treatments were similar but decreased (12%; P < 0.01) relative to P1. Except for increased milk fat concentration (19%; P = 0.03), LPS infusion had little or no effect on SCC, milk protein, and lactose content. Based upon body temperature and production variables, this data supports that lactating Holstein dairy cows become incredibly tolerant to chronic and exponentially increasing amounts of infused LPS.