There are many negative health concerns associated with insulin resistance in the horse, including an increased risk for development of the debilitating condition, laminitis. With a growing awareness of the prevalence of insulin resistance in these animals, it is becoming increasingly important to investigate its possible causes and consequences, in particular regarding the role of inflammation in these individuals. To accomplish this, 16 similarly managed mixed sex and mixed breed horses were selected. Of these, 8 were metabolically normal and 8 were affected by Equine Metabolic Syndrome (EMS), whose three main defining characteristics include; insulin resistance, a predisposition to or history of laminitis, and general or regional adiposity. An oral sugar challenge test was performed to determine metabolic and inflammatory responses to challenge in EMS horses compared to metabolically normal controls. Peripheral blood was collected by jugular venipuncture prior to, 60 and 240 minutes post oral sugar administration. Serum was used for analysis of circulating insulin and glucose concentrations. Heparinized plasma was used to isolate peripheral blood mononuclear cells (PBMCs) for proinflammatory cytokine protein and gene expression analysis via flow cytometry and RT-PCR, respectively. Results were analyzed using the Proc mixed procedure in SAS 9.4 (SAS Institute Inc., Cary, NC, USA) and results considered statically significant when p < 0.05. As expected, horses had a significant increase in metabolic parameters in response to oral sugar administration with EMS horses having an exaggerated response. However, EMS and control horses had significantly different, even opposing, inflammatory responses to challenge. These data provide new information regarding the possible effects of insulin resistance as it relates to inflammation, and opens up new avenues of inquiry as to potential mechanisms for the predisposition to and pathogenesis of laminitis.