To better understand the beneficial effects of rumen-protected choline (RPC), rumen-protected Met (RPM), and their interaction, our objective was to determine if these nutrients modify the choline metabolite profile of plasma and milk or influence hepatic expression of genes associated with choline, Met, and lipid metabolism in periparturient cows. Cows (25 primigravid, 29 multigravid) were blocked by expected calving date and parity and assigned to one of 4 treatments: CON (no RPC or RPM); CHO (60 g/d RPC); MET (12 g/d RPM prepartum; 18 g/d RPM postpartum); or CHO + MET. Treatments were applied daily as a top-dress from 19 ± 2 d prepartum through 35 d in milk (DIM). Blood and milk samples were collected at 7 and 14 DIM for analysis of choline metabolites, including 16 species of phosphatidylcholine (PC). Liver collected at 7 DIM from multiparous cows was used for gene expression analysis. Blood and milk data were analyzed using a mixed model that included fixed effects of choline, Met, and day (7 or 14 DIM), and random effects of cow and block. Pretreatment blood metabolite concentrations were included as covariates. RPC reduced milk betaine yield in multiparous cows (P = 0.05) and tended to increase it in primiparous cows (P = 0.09), but these changes were driven by changes in milk yield. RPC and RPM increased yields of 4 and 3 PC species by an average of 101 (P ≤ 0.02) and 81% (P ≤ 0.03), respectively, for multiparous cows. RPM also reduced plasma free choline concentration by 10% (P = 0.03), while RPC tended to increase glycerolphosphocholine concentration by 58% in multiparous cows (P = 0.07). When fed without RPM, RPC tended to increase hepatic expression of betaine-homocysteine methyltransferase (CHO x MET: P = 0.09) and phosphate cytidylyltransferase 1 choline α (CHO x MET: P = 0.10). Additionally, RPC tended to decrease expression of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (P = 0.10) and peroxisome proliferator activated receptor α (P = 0.08). Our results indicate that both Met and choline have different effects on choline metabolism in periparturient cows and that these effects vary between primi- and multiparous cows.