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Invasive Salmonella Typhimurium (<i>S</i>. Typhimurium) causes lethal bloodstream infections (BSI), yet its molecular mechanisms remain unclear. We compared serum resistance and cellular invasive capabilities between invasive and non-invasive <i>S</i>. Typhimurium. Invasive strains exhibited significantly enhanced serum resistance (&gt;17-fold survival in 75% isolates) and HeLa cell invasive ability (minimum bacterial loads 3.93 × 10⁵ CFU/mL) compared to non-invasive strains (&lt; 9.8-fold survival; maximum bacterial loads 1.47 × 10⁵ CFU/mL). We next performed pan-genomic analysis and virulence gene database comparisons to elucidate the genetic mechanisms underlying robust serum resistance in invasive <i>S</i>. Typhimurium. We identified 15 differential genes unique to invasive <i>S</i>. Typhimurium, among which the <i>StiP</i> deletion strain (263<i>ΔStiP</i>) showed the greatest serum resistance reduction (2.49-fold). We further explored the role of <i>StiP</i> in host blood environment adaptation and found that 263<i>ΔStiP</i> displayed 3.12-fold reduced HeLa cell adhesion, 3.74-fold lower HeLa cell invasion, 1.92-fold decreased intra-macrophage survival, and 50% reduced serum resistance versus wild-type 263 (WT263), collectively indicating that <i>StiP</i> is critical for host blood environment adaptation in invasive <i>S</i>. Typhimurium. Mechanistically, <i>StiP</i> upregulates the membrane protein Alx, which recruits complement factor I (CFI) to accelerate C3b degradation, thereby inhibiting classical complement pathway activation and enhancing invasive <i>S</i>. Typhimurium complement evasion. In vivo, 263<i>ΔStiP</i>-infected mice exhibited 5-, 7-, and 4-fold lower bacterial loads in blood, liver, and spleen (P &lt; 0.001), respectively, with reduced pathological damage versus WT263. Thus, this study elucidates the <i>StiP</i>-Alx axis mediating complement evasion in invasive <i>S</i>. Typhimurium.