We examined effects of prepartum (3 wk) and postpartum (3 wk) supplementation of rumen-protected lysine (RPLys; USA Lysine; Kemin Industries Inc.; 42% Lys bioavailability) and methionine (RPMet; MetiPEARL; Kemin Industries Inc.; 29% Met bioavailability) on performance of transition cows. Holstein prepartum cows (88) were blocked by parity and expected calving and assigned to 1 of 4 treatments arranged factorially. Treatments were a prepartum diet with (Pre+) or without (Pre−) RPLys (10 g digestible Lys) and RPMet (4 g digestible Met) followed by postpartum diet with (Post+) or without (Post−) RPLys (26 g digestible Lys) and RPMet (11 g digestible). Prepartum, only 2 treatments were applied (Pre+ and Pre−; n = 44/treatment), but postpartum cows received treatments of Pre−Post−, Pre−Post+, Pre+Post−, or Pre+Post+ (n = 22/treatment). Data were analyzed using the MIXED procedure of SAS where block within parity was random effect and treatment, parity, day, and their interactions were fixed effects. During the prepartum period, treatment did not affect DMI and BW. During the postpartum period, milk protein content was greater (3.23 vs. 3.11%; P = 0.01) for Post+ compared with Post- independent of prepartum treatment. However, DMI, BW, milk yield, and yields of milk components were not affected by Post+ vs. Post−. No effects of prepartum treatment on postpartum performance were observed. However, Pre+ decreased logSCC (4.60 vs. 4.83/mL; P = 0.01) compared with Pre− and this effect continued (P = 0.04) for 10 wk after supplementation of RPLys and RPMet ceased. Prepartum cows had or tended to have greater (P < 0.10) plasma concentrations of Lys, Met, and branched-chain amino acids for Pre+ vs. Pre−. Cows on Post+ tended to have greater (P = 0.09) plasma Lys but have similar Met compared with Post−. In conclusion, effects of prepartum and postpartum supplementation of RPLys and RPMet on performance were minimal except milk protein content. However, prepartum supply of RPLys and RPMet may have potential to lower SCC postpartum.