We investigated the impact of a rumen-bypass protein supplement on growth performance, plasma and urinary N concentration, hepatic mitochondrial protein complexes, and hepatic mRNA expression of immune genes of beef steers with negative or positive residual feed intake (RFI) phenotype. Forty crossbred beef steers with an average body weight (BW) of 492 ± 36 kg were subjected to a generalized randomized block design over a 42-day experimental period. This study followed a 2 × 2 factorial arrangement of treatments. The factors evaluated were: 1) RFI classification (low-RFI (-2.12 kg/d) vs. high-RFI (2.02 kg/d), and 2) rumen-bypass protein supplement: rumen-bypass protein supplement (RCP; 227 g/steer/d) vs. control diet (CON; 0 g/d), resulting in four distinct treatments: Low-RFI-CON (n = 10), low-RFI-RCP (n = 10), high-RFI-CON (n = 10), and high-RFI-RCP (n = 10). The rumen-bypass protein supplement (84% CP) is a mixture of hydrolyzed feather meal, porcine blood meal, and DL-methionine hydroxy analogue. The beef steers were stratified by BW and randomly assigned to treatments and housed in four pens (1 treatment/pen) equipped with two GrowSafe feed bunks each to measure individual DMI. Body weight was measured every 7 d. Liver tissue samples were collected on d 42 from all the beef steers. These samples were used for mRNA expression analysis of 16 immune-related genes and for evaluating the mitochondrial protein complexes I - V. No significant effects due to RCP supplementation or RFI × RCP interactions (P > 0.05) were observed for ADG and DMI. However, compared to high-RFI steers, low-RFI steers showed a trend towards reduced DMI (12.9 vs. 13.6 kg/d; P = 0.07) but ADG was similar for the two RFI groups. Regardless of RFI status, supplemental RCP increased blood urea nitrogen (BUN) (P = 0.01), with a lower BUN concentration in low-RFI steers compared to high-RFI ones. A tendency for interaction (P = 0.07) between RFI and RCP was detected for urinary N concentrations; feeding RCP diet increased the urinary concentration of urea-N in high-RFI beef steers (209 vs. 124 mM), whereas the concentration was lower than that of the CON group for low-RFI beef steers (86 vs. 131 mM). Interactions of RCP and RFI were observed (P ≤ 0.05) for mitochondrial activities of complexes IV, V, and mRNA expressions of some immune genes such as TLR2, TLR3, and IL23A. In conclusion, while RCP supplementation didn't alter growth performance, its observed effects on hepatic immune gene expression, mitochondrial protein complexes, BUN, and urinary urea nitrogen depended on the beef steers' RFI phenotype. Further studies are warranted to understand the mechanisms underpinning the interactions between RCP supplementation and RFI status.