The liver plays a central role in allowing dairy cattle to make a successful transition into lactation. In liver, as in other tissues, extracellular nucleotides and nucleosides trigger cellular responses through adenosine and ATP receptors. Adenosine triphosphate and certain nucleotides serve as signals that can heighten purinergic receptor activation in several pathologic processes. We evaluated the mRNA expression of genes associated with the purinergic signaling network in liver tissue during the peripartal period. Seven multiparous Holstein cows were dried off at d -50 relative to expected parturition and fed a controlled-energy diet (net energy for lactation = 1.24 Mcal/kg of DM) for ad libitum intake during the entire dry period. After calving, all cows were fed a common lactation diet (net energy for lactation = 1.65 Mcal/kg of DM) until 30 DIM. Biopsies of liver were harvested at d -10, 7, and 21 for mRNA expression of 9 purinergic receptors, 7 ATP and adenosine transport channels, and 10 enzymes associated with ATP hydrolysis. Blood collected at d -21, -10, 7, 14, and 21 was used to measure concentrations of inflammation and oxidative stress biomarkers. The expression of type 1 purinergic receptors (ADORA2A and ADORA3), several nucleoside hydrolases [ectonucleoside triphosphate diphosphohydrolase 7 (ENTPD7), ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2), ENPP3, and adenosine deaminase (ADA)], and a type 2 purinergic receptor (P2RX7) was downregulated after calving. In contrast, the expression of type 2 purinergic receptors (P2RX4 and PR2Y11), an ATP release channel (gap junction hemichannel GJB1), and an adenosine uptake protein (SLC29A1) followed the opposite response, increasing after calving and remaining elevated through 21 d. Haptoglobin, ceruloplasmin, and reactive oxygen metabolite concentrations increased gradually from d -21 d through at least d 7. The opposite response was observed for albumin, paraoxonase, α-tocopherol, and nitric oxide, which decreased gradually to a nadir at 7 and 14 d. Our results suggest that alterations after calving of the expression of hepatic purinergic signaling genes could be functionally important because in nonruminants, they play roles in bile formation, glucose metabolism, cholesterol uptake, inflammation, and steatosis. The correlation analysis provided evidence of a link between purinergic signaling genes and biomarkers of inflammation and oxidative stress.