Background: Identifying biomarkers to aide in the diagnosis and prognostication of sepsis in dogs would be valuable to veterinarians.Objective: To compare plasma inflammatory mediator concentrations among dogs with sepsis, noninfectious systemic inflammatory response syndrome (NSIRS), and healthy dogs.Animals: Dogs with sepsis (n = 22), NSIRS (n = 23), and healthy dogs (n = 13) presenting to the intensive care unit (ICU) at a veterinary teaching hospital.Methods: Prospective observational study. Clinical parameters were recorded for each dog and plasma tumor necrosis factor (TNF) bioactivity and concentrations of interleukin (IL)-6, CXC chemokine ligand (CXCL)-8 and IL-10 were determined at ICU presentation.Results: Dogs with sepsis and NSIRS were significantly more likely to have measurable TNF activity (sepsis 20/22; NSIRS 19/20; healthy 0/13) and IL-6 concentration (sepsis 12/22; NSIRS 15/23; healthy 2/13), than healthy dogs. Healthy dogs (9/13) were significantly more likely to have measurable plasma IL-10 concentrations than dogs with sepsis (4/19), but not NSIRS (7/20). None of the inflammatory mediators evaluated had optimal sensitivity or specificity for the diagnosis of sepsis. Twelve of 22 dogs with sepsis and 15/23 dogs with NSIRS survived to discharge; none of the measured biomarkers correlated with survival to discharge.Conclusions and Clinical Importance: Sepsis and NSIRS are associated with increased production of the proinflammatory cytokines TNF and IL-6. In addition, sepsis is associated with decreased production of the anti-inflammatory cytokine IL-10. Despite this, plasma TNF, IL-6, CXCL-8, and IL-10 measured at ICU presentation do not appear to be valuable biomarkers to differentiate sepsis from NSIRS, or predict hospital outcome.