We studied the effects of two Salmonella enterica serovar Typhimurium (host-adapted) strains (14028 and 4/74) and three S. Choleraesuis (non-host-adapted) strains (A50, A45, and B195) in human monocytes between 2 and 24 h postinfection (p.i.) to investigate whether differences in immune response may explain the much higher prevalence of sepsis in individuals infected with S. Choleraesuis. Both serovars significantly increased the production of cytokines associated with acute sepsis (tumor necrosis factor alpha [TNF-α], interleukinβ[IL-β], and IL-6), but temporal differences occurred between these serovars and between different S. Choleraesuis strains. Generally, all S. Choleraesuis strains induced significantly higher production of inflammatory cytokines than S. Typhimurium strains (P< 0.01 to 0.05). All S. Choleraesuis strains very significantly increased IL-10 production by monocytes at 6 and 24 h p.i. in comparison to S. Typhimurium strains (P < 0.01). In addition, ~80% of monocytes were viable at 24 h p.i. with S. Choleraesuis A50, compared to only ~40% following S. Typhimurium infection. Using S. Typhimurium 14028 and S. Choleraesuis A50 as examples of these two serovars, we also showed differential expression of genes within the Janus tyrosine kinase (JAK) and signal transducer and activator of transcription (STAT) (JAK/STAT) pathway via quantitative PCR (qPCR) microarray analysis. High serum IL-10 concentration and monocyte survival have been reported as markers of the development of human sepsis. We therefore conclude that high production of IL-10 by monocytes may, in part, explain the greater propensity for S. Choleraesuis to induce human sepsis and that this may be greater in strains such as A50, which induces both high IL-10 production and monocyte survival.