Abstract Functional amino acid (FAA) supplementation improves growth performance and immune status of weaned pigs. The objective was to determine the effects of birth weight and FAA supplementation in the post-weaning period on the response of pigs to a subsequent Salmonella (ST) challenge. Thirty-two low (1.09±0.11 kg; LBW) and normal birth weight (1.58±0.11 kg; NBW) pigs were assigned to a nursery feeding program for 4 wk in a 2 × 2 factorial with factors of birth weight category (LBW vs. NBW) and basal (FAA–) or supplemented FAA profile (FAA+; Thr, Met, and Trp at 120% of requirements). Pigs were then placed onto a grower diet and, after a 7-d adaptation period, were inoculated with ST (2.2 × 109 CFU/mL) and monitored for 7 d post-inoculation. Growth performance, rectal temperature, gut health, ST fecal shedding and translocation, and blood parameters were measured pre- and post-inoculation. Inoculation with ST increased rectal temperature (39.7 vs. 38.9±0.5 oC) and overall rectal temperature was higher in LBW compared with NBW pigs (39.6 vs. 39.0±0.5 oC; P< 0.05). Salmonella shedding (1.8 vs. 2.3±0.1 score) and translocation to spleen (1.3 vs. 2.5±0.1 score) were less in NBW-FAA+ than NBW-FAA- pigs (P< 0.05). Post-inoculation weight gain was greater in NBW-FAA+ compared with the other groups (0.57 vs. 0.45±0.03 kg/d; P< 0.05). Post-inoculation haptoglobin (d 4; 1.0 vs. 0.7±0.1 g/L) and colonic myeloperoxidase (d 7; 4.3 vs. 2.5±0.6 µU/mL) were greater in LBW-FAA- pigs compared with the other groups (P< 0.05). On d 4 post-inoculation, plasma superoxide dismutase was less in LBW- FAA+ than in LBW-FAA- (60.5 vs. 93.3±7.7 mU/mL; P< 0.05). Reduced:oxidized glutathione at d 7 post-inoculation was greater in NBW compared with LBW pigs (2.5 vs. 1.7±0.3; P< 0.05). In conclusion, negative effects of Salmonella infection are ameliorated with supplementation of FAA to a greater extent in NBW than in LBW pigs.