The metabolic phenomenon of ketosis in dairy cows has remained ambiguous, casting uncertainty over our understanding and its real implications. Ketosis, commonly defined as blood β-hydroxy-butyrate (BHB) ≥ 1.2 mM (i.e., hyperketonemia), has been observationally connected to the onset of peripartal metabolic disorders (e.g., infectious diseases, fatty liver), and reduced milk yield in dairy cows. Although BHB is currently used as standard biomarker for the prediction of negative health and performance outcomes during the peripartum, the nature of this relationship is ambiguous. In contraposition, recent discoveries in mammalian biology indicate BHB as therapeutic metabolite (e.g., alleviation of inflammation and oxidative stress). Our overreaching goal was to study the effects of BHB on dairy cow metabolism and health. In our first study, 6 multiparous (parity = 2.8 ± 0.9) Holstein mid-lactation dairy cows (128 ± 52 days in milk; DIM), were enrolled in a study to evaluate a ketogenic diet using calcium butyrate (—CaBu—; a ruminal ketone precursor) against an un-supplemented control (Control) in a crossover arrangement of treatments. The CaBu resulted in nutritional ketosis (P < 0.05) with blood BHB levels of 0.2 mM higher relative to Control. Although CaBu resulted in reduced dry matter intake (DMI; P < 0.05), milk production was not affected (P > 0.40), and feed efficiencies were improved (P < 0.05) relative to Control. No differences in glucose, NEFA, respiration rates, pain scores, or rectal temperatures were observed between treatments. In the second experiment, 8 multiparous Holstein (2.75 ± 0.89) mid-lactation dairy cows (140 ± 48 DIM), feed ad libitum, were enrolled in a in a crossover arrangement of treatments. The aim of the study was to evaluate the effect of ketones by intravenous infusion of either Na-BHB solution (2.5mM; EK) to sustain hyperketonemia —BHB > 1.2 mM and < 3.0 mM—, or NaCl as a control (2.5mM; Control) over a 72h period. A systemic lipopolysaccharide (LPS) challenge (E. coli 055:B5; 0,085 g/kg BW,) was intravenously administered at h 60 from infusion start. Cows sustained hyperketonemia throughout the 72h experimental period (1.4 BHB mM vs. 0.7 BHB mM in EK vs. Control, respectively). While DMI and milk production were not affected by the BHB infusion, the combination with the LPS challenge resulted in reductions of 20.8% (P < 0.05) and 40.1%, (P = 0.14) for both measurements in EK vs. Control, respectively. No differences were detected in the glucose and NEFA concentrations, but insulin was higher 46.6% (P < 0.05) in EK group. Among the immune markers, IL-1 was 30.8% higher (P < 0.05) in the EK group, and not differences were detected in TNF, IL-10, CRP, and caspase-1. As expected, the LPS challenge induced increased respiration rates, temperature, and pain scores over the time course of the evaluation (P < 0.001); however, respiration rates tended to be reduced in 8.4% (P < 0.1) and rectal temperature increased in 0.3% (P < 0.05) by the BHB treatment (P < 0.05). Our results are indicative that, in the absence of an immune challenge, hyperketonemia results in no negative impact on cow productivity and health. These data add support to our hypothesis that cofactors other than ketones may be necessary for the development of negative trajectories of health and performance of lactating dairy cows. Future studies will be required to confirm that BHB hyperketonemia metabolic effects could differ from ketosis disorder in dairy cows.