Activation of immune response pathway is energy demanding. We tested the hypothesis that negative energy balance will curtail the liver's capacity to evoke an immune response in rainbow trout (Oncorhynchus mykiss). Fish were either fed or fasted for 118 d and challenged with lipopolysaccharide (LPS) to determine the liver capacity to elicit an immune response. Fasting led to negative specific growth rate, reduced tissue metabolite levels, and higher transcript abundance of SOCS-2. LPS treatment increased the liver transcript abundances of IL-1β and IL-8 and serum amyloid protein A, while SOCS-2 was reduced. LPS lowered plasma cortisol level only in the fasted fish, but did not affect liver glucocorticoid or mineralocorticoid receptor protein expressions. Extended fasting did not suppress the liver capacity to evoke an immune response. Upregulation of liver SOCS-2 may be playing a key role in the energy repartitioning, thereby facilitating immune response activation despite extended fasting in trout.