Abstract Immune system stimulation (ISS) modifies protein and amino acid (AA) metabolism in animals and humans. During ISS, AA are redirected away from growth and reproduction towards mounting an immune response. This redirection can impact AA requirements both qualitatively (i.e., the AA ratio) and quantitatively. Special attention has been given to sulfur-containing amino acid (SAA; Met + Cys) metabolism during ISS, due to their roles as precursors for the synthesis of proteins and metabolites that are involved in the immune response. A series of studies were conducted to investigate the impact of ISS on various aspects of SAA utilization, including ileal digestibility, plasma kinetics, the glutathione (GSH) synthesis rate, the irreversible loss of Cys, and dietary total SAA requirements. In all of the studies, pigs were feed restricted (≥ 2 times the maintenance requirement for ME) to eliminate the confounding effect of ISS on feed intake. Results indicated that ISS alters SAA metabolism and increases SAA requirements per unit of protein deposition. The latter occurs due to increased maintenance requirements for SAA during ISS. The results also showed that the enhanced maintenance requirement for SAA occurs mainly as a result of increased SAA utilization, mainly Cys, for the synthesis of immune system metabolites, such as GSH and acute-phase proteins, as well as the increased catabolism of Cys to taurine. In addition, we found that ISS increases the dietary Met-to-total SAA ratio in pigs, suggesting an enhanced preferential demand for dietary Met during ISS, perhaps to support an elevated rate of transsulfuration. Collectively, our findings point toward a need for developing an optimal dietary AA profile for diseased pigs.