Soybean protein ingredients (SB as soybean meal; SBM and soya protein concentrates; SBP) are widely used in pig diets; however they may also promote acute intestinal inflammation and affect gut mucosal integrity and performance. Several beneficial effects of nucleotide supplementation on gut immune function, inflammation and diarrhea has been reported, which could reduce the negative effects SB in piglets. The aim of the present work was to study the effect of including nucleotides (Nucleoforce Piglets, Bioibérica, SA) in diets containing different levels of SB on acute inflammation process and early performance of weaned piglets. Two hundred forty 28-d-old piglets [Pt × (LD × LW)] were distributed into 24 pens (10 pigs/ pen) according to the initial BW following a RCBD. Two pre-starter diets differing in the SB content as protein source (Low or High) formulated to contain 10.3 MJ/kg of NE, 19.5% CP and 1.28% Lys were supplemented with or without nucleotides (500 mg/kg) following a 2 × 2 factorial arrangement. High SB diet contained 15% of extruded soybeans, 6.82% SBM and 5.62% SBP; while Low SB diet was obtained by partly replacing SB ingredients with fish meal (8.44%) and animal plasma (2.5%) according to their protein content. Feed was offered ad libitum in mash form. Individual animal weight and feed disappearance were recorded at d 28 and 42 of live. Blood samples were collected on d 7 to determine TNFα as inflammation marker. Data was analyzed with ANOVA following a 2 × 2 factorial arrangement with GLM procedure of SAS. Higher BW (9.59 vs 9.09 kg; P = 0.03), ADFI (205 vs 167 g/d; P = 0.002) and ADG (140 vs 103 g/d: P = 0.04) was observed for Low SB diet than high SB diet, independently of the nucleotide supplementation. An interaction between SB inclusion in the diet and nucleotide supplementation was observed (P = 0.04) reflecting that nucleotides promote a decrease of TNFα in High SB group (95.1 vs 67.4 pg/mL) but not in Low SB group (60.3 vs 70.1 pg/mL) without and with nucleotides, respectively. It is concluded that nucleotide supplementation in diets containing high inclusion of soybean meal and soybean protein products reduces acute inflammation process.